Substituted tetrahydroisoquinoline compounds useful as gpr120 agonists

ABSTRACT

The present invention relates to a compound represented by formula (I) and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing diabetes, hyperlipidemia, obesity, NASH, inflammation related disorders, and related diseases and conditions. The compounds are useful as agonists of the G-protein coupled receptor GPR120. Pharmaceutical compositions and methods of treatment are also included.

BACKGROUND OF THE INVENTION

The present invention relates to substituted chromane derivatives thatare useful in the pharmaceutical field. The compounds act as GPR120receptor function regulating agents (modulators), which are useful asdrugs for treating and/or preventing diabetes, obesity, hyperlipidemia,and inflammation related disorders.

GPR120, a G protein-coupled receptor, causes intracellular signalingthrough binding with unsaturated long chain fatty acids, such asalpha-linoleic acid, to induce various biological reactions. Actions ofGPR120 and its ligand(s) have been reported to promote secretion ofglucagon-like-peptide-1 (“GLP-1”) functions to reduce blood glucoselevel in gastrointestinal cell lines (see Nature Medicine, 2005, 11(1),90-94). GLP-1, which is a peptide hormone, has been found to induceinsulin secretion depending on a blood glucose level. GLP-1 is alsosuggested to be efficacious for delaying the apoptosis of beta cells intype 11 diabetes mellitus.

GPR120 is expressed in adipocytes. GPR120 has been found to beincreasingly expressed by adipose differentiation induction. Inaddition, actions of GPR120 and its ligand have been reported tosuppress lipolysis in adipose-differentiated cells. A high blood lipidlevel is known to be one of the causes of insulin resistance.Suppression of lipolysis by a GPR120 agonist is thus expected todecrease the levels of free fatty acids in blood to normalize bloodlipid levels, resulting in improvement in insulin resistance.

GPR120 is also expressed in the pituitary gland, and a GPR120 ligand isreported to suppress adrenocorticotropic hormone secretion.Adrenocorticotropic hormone promotes glucocorticoid secretion downstreamthereof to induce action such as promotion of gluconeogenesis in theliver, inhibitory action against glucose uptake in muscle and peripheraltissue, lipolysis in adipose tissue or release of fatty acids orglycerol. Accordingly, GPR120 is considered to exhibit hypoglycemicaction or blood lipid lowering action via suppression action againstadrenocorticotropic hormone secretion even in the center.

Recently, GPR120 has been shown to play a role in obesity in both miceand humans. GPR120 knockout mice fed a high fat diet developed obesity,glucose intolerance and fatty liver with decreased adipocytedifferentiation and lipogenesis and enhanced hepatic lipogenesis. In thestudy, insulin resistance in such mice was associated with reducedinsulin signaling and enhanced inflammation in adipose tissue. Inhumans, GPR120 expression in adipose tissue is significantly higher inobese individuals than in lean controls (See Ichimura, et al., Nature,2012, 483, 350-54; and Cintra. et al., Plos One, 2012, 7(1), 1-15).

GPR120 has also been shown to play a role in inflammation. Wild-typemice treated with omega-3 fatty acids inhibited macrophage-inducedtissue inflammation and enhanced systemic insulin sensitivity. However,this effect was not observed in GPR120 knockout mice (See Oh, et al.,Cell, 2010, 142, 687; and Talukar. et al., Trends in PharmacologicalSciences, 2011, 32(9), 543-550).

In light of the above description, a compound having GPR120 agonistactivity is considered to be useful as an agent for treating and/orpreventing diabetes mellitus, obesity, hyperlipidemia, fatty liver(including non-alcoholic steatohepatitis or NASH), and inflammationrelated disorders.

SUMMARY OF THE INVENTION

The present invention relates to compounds represented by formula I:

as well as pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising a compound of formula I.

The present invention further relates to methods of treating diabetes,obesity, hyperlipidemia, NASH, inflammation related disorders, andrelated diseases and conditions, comprising administering a compound offormula I to a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is

(1) bond,

(2) (C₁₋₂)alkyl, or

(3) halo(C₁₋₂)alkyl;

ring A is

(1) aryl,

(2) 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatomsindependently selected from N, O and S, or

(3) 9- or 10-membered fused heteroaryl containing 1, 2, or 3 heteroatomsindependently selected from N, O, and S;

R¹ is

-   -   (1) bond,    -   (2) (C₁₋₆)alkyl,    -   (3) —O—(C₁₋₆)alkyl-, or    -   (4) (C₃₋₆)cycloalkyl;

R² is

-   -   (1) hydrogen,    -   (2) hydroxy,    -   (3) COOH,    -   (4) tetrazole,    -   (5) hydroxyisoxazole,    -   (6) triazole,    -   (7) C(O)NH₂,    -   (8) C(O)NHC₁₋₆alkyl,    -   (9) C(O)NHC₃₋₆cycloalkyl,    -   (10) C(O)NHC₂₋₅cycloheteroalkyl,    -   (11) C(O)NH-aryl,    -   (12) C(O)NH-heteroaryl,    -   (13) SO₂C₁₋₆alkyl,    -   (14) SO₂C₃₋₆cycloalkyl,    -   (15) SO₂C₂₋₅cycloheteroalkyl,    -   (16) SO₂-aryl, or    -   (17) SO₂-heteroaryl:

R³ is

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) cyano, or    -   (4) (C₁₋₃)alkyl;

R⁴ is

-   -   (1) hydrogen,    -   (2) (C₁₋₃)alkyl,    -   (3) halo(C₁₋₃)alkyl, or    -   (4) halogen;

R⁵ is

-   -   (1) cyano,    -   (2) (C₁₋₃)alkyl,    -   (3) halo(C₁₋₃)alkyl,    -   (4) (C₁₋₃)alkoxy,    -   (5) halo(C₁₋₃)alkoxy, or    -   (6) halogen;

R⁶ is

-   -   (1) (C₁₋₃)alkoxy,    -   (2) halo(C₁₋₃)alkoxy,    -   (3) halo(C₁₋₃)alkyl,    -   (4) (C₃₋₆)cycloalkyl,    -   (5) (C₃₋₆)cycloalkyl-O—,    -   (6) (C₃₋₆)cycloalkyl-S—,    -   (7) (C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-,    -   (8) (C₃₋₆)cycloalkyl-halo(C₁₋₂)alkyl-,    -   (9) phenyl,    -   (10) 5- to 6-membered heteroaryl-O— wherein the heteroaryl        contains 1, 2, or 3 heteroatoms independently selected from N, O        and S, or    -   (11) 5- to 6-membered heteroaryl- wherein the heteroaryl        contains 1, 2, or 3 heteroatoms independently selected from N, O        and S,        wherein alkyl, cycloalkyl, phenyl and heteroaryl are        unsubstituted or substituted with 1-3 substituents selected from        (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy,        and halogen;        n is 0, 1, 2 or 3;        m is 0 or 1;        p is 0, 1, 2 or 3; and        q is 0, 1, or 2.

In one embodiment of the present invention, X is a bond, (C₁₋₂)alkyl, orhalo(C₁₋₂)alkyl.

In another embodiment of the present invention, X is a bond, or(C₁₋₂)alkyl.

In another embodiment of the present invention, X is a bond, or CH₂.

In another embodiment of the present invention, X is a bond.

In another embodiment of the present invention, X is CH₂.

In another embodiment of the present invention, ring A is aryl, 5- or6-membered heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O and S, or 9- or 10-membered fused heteroarylcontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS. In a class of this embodiment, ring A is phenyl, pyridine,pyrimidine, pyrazole, pyrazine, isothiaozole, or benzisoxazole.

In another embodiment, ring A is 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O and S, or 9- or10-membered fused heteroaryl containing 1, 2, or 3 heteroatomsindependently selected from N, O, and S. In a class of this embodiment,ring A is pyridine, pyrimidine, pyrazole, pyrazine, isothiaozole, orbenzisoxazole.

In another embodiment, ring A is 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O and S. In aclass of this embodiment, ring A is pyridine, pyrimidine, pyrazole,pyrazine, or isothiaozole.

In another embodiment, ring A is 9- or 10-membered fused heteroarylcontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS. In a class of this embodiment, ring A is benzisoxazole.

In another embodiment, ring A is aryl. In a class of this embodiment,ring A is phenyl.

In another embodiment of the present invention, R¹ is a bond,(C₁₋₆)alkyl, —O—(C₁₋₆)alkyl-, or (C₃₋₆)cycloalkyl. In a class of thisembodiment, R¹ is a bond, CH₂CH₂, CH₂CH₂CH₂, CH(CH₃)CH₂, CH₂CH(CH₃),CH₂CH₂CH₂CH₂, CH(CH₃)CH₂CH₂CH₂, OCH₂CH₂, OCH₂CH₂CH₂, OCH₂CH₂CH₂CH₂, orcycloalkyl.

In another embodiment of the present invention, R¹ is a bond,—O—(C₁₋₆)alkyl-, or (C₃₋₆)cycloalkyl. In a class of this embodiment, R¹is a bond, OCH₂CH₂, OCH₂CH₂CH₂, OCH₂CH₂CH₂CH₂, or cycloalkyl.

In another embodiment of the present invention, R¹ is a bond.

In another embodiment of the present invention, R¹ is —O—(C₁₋₆)alkyl-,or (C₃₋₆)cycloalkyl. In a class of this embodiment, R¹ is OCH₂CH₂,OCH₂CH₂CH₂, OCH₂CH₂CH₂CH₂, or cycloalkyl.

In another embodiment of the present invention, R¹ is —O—(C₁₋₆)alkyl-.In a class of this embodiment, R¹ is OCH₂CH₂, OCH₂CH₂CH₂, orOCH₂CH₂CH₂CH₂.

In another embodiment of the present invention, R¹ is (C₃₋₆)cycloalkyl.In a class of this embodiment, R¹ is cyclopropyl.

In another embodiment of the present invention, R¹ is (C₁₋₆)alkyl. In aclass of this embodiment, R¹ is CH₂CH₂, CH₂CH₂CH₂, CH(CH₃)CH₂,CH₂CH(CH₃), CH₂CH₂CH₂CH₂, or CH(CH₃)CH₂CH₂CH₂.

In another embodiment of the present invention, R¹ is a bond,

In another embodiment of the present invention, R² is hydrogen, hydroxy,COOH, tetrazole, hydroxyisoxazole, triazole, C(O)NH₂, C(O)NHC₁₋₆alkyl,C(O)NHC₃₋₆cycloalkyl, C(O)NHC₂₋₅cycloheteroalkyl, C(O)NH-aryl,C(O)NH-heteroaryl, SO₂C₁₋₆alkyl, SO₂C₃₋₆cycloalkyl,SO₂C₂₋₅cycloheteroalkyl, SO₂-aryl, or SO₂-heteroaryl.

In another embodiment of the present invention, R² is hydrogen, hydroxy,COOH, tetrazole, hydroxyisoxazole, or triazole.

In another embodiment of the present invention, R² is hydrogen, hydroxy;COOH, or tetrazole.

In another embodiment of the present invention, R² is hydrogen, hydroxy,or tetrazole.

In another embodiment of the present invention, R² is hydrogen.

In another embodiment of the present invention, R² is hydroxyl.

In another embodiment of the present invention. R² is tetrazole.

In another embodiment of the present invention, R² is COOH.

In another embodiment of the present invention, R³ is hydrogen, halogen,cyano, or (C₁₋₃)alkyl. In a class of this embodiment, R³ is hydrogen, F,Cl, cyano, or CH₃.

In another embodiment of the present invention, R³ is hydrogen, halogen,or (C₁₋₃)alkyl.

In a class of this embodiment, R³ is hydrogen, F, Cl, or CH₃.

In another embodiment of the present invention, R³ is hydrogen, orhalogen. In a class of this embodiment, R¹ is hydrogen, F, or Cl. Inanother class of this embodiment, R³ is hydrogen, or F.

In another embodiment of the present invention, R⁴ is hydrogen,(C₁₋₃)alkyl, halo(C₁₋₃)alkyl, or halogen.

In another embodiment of the present invention. R⁴ is hydrogen or(C₁₋₃)alkyl. In a class of this embodiment, R⁴ is hydrogen, or CH₃.

In another embodiment of the present invention, R⁴ is (C₁₋₃)alkyl. In aclass of this embodiment, R⁴ is CH₃.

In another embodiment of the present invention, R⁴ is hydrogen.

In another embodiment of the present invention, R⁵ is cyano,(C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, orhalogen.

In another embodiment of the present invention, R⁵ is cyano,(C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, or halogen. In a class ofthis embodiment, R⁵ is cyano, CH₃, CF₃, CHF₂, OCH₃, F, or Cl.

In another embodiment of the present invention, R⁵ is cyano or halogen.In a class of this embodiment, R⁵ is cyano, F, or Cl.

In another embodiment of the present invention, R⁶ is halo(C₁₋₃)alkoxy;halo(C₁₋₃)alkyl, (C₃₋₆)cycloalkyl, (C₃₋₆)cycloalkyl-O—,(C₃₋₆)cycloalkyl-S—, (C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-, phenyl, 5- to6-membered heteroaryl-O— wherein the heteroaryl contains 1, 2, or 3heteroatoms independently selected from N, O and S, or 5- to 6-memberedheteroaryl- wherein the heteroaryl contains 1, 2, or 3 heteroatomsindependently selected from N, O and S, wherein alkyl, cycloalkyl,phenyl and heteroaryl are unsubstituted or substituted with 1-3substituents selected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy,halo(C₁₋₃)alkoxy, and halogen. In a class of this embodiment of thepresent invention, R⁶ is OCF₃, CF₃, cyclopropyl, cyclobutyl-O—,cyclobutyl-S—, cyclobutyl-CH₂—, phenyl, thiazolyl-O—, pyridyl-O—,pyrazinyl-O—, or thienyl, wherein cyclopropyl, cyclobutyl, phenyl,thiazolyl, pyridyl, pyrazinyl and thienyl are unsubstituted orsubstituted with 1-3 substituents selected from OCH₃, CHF₂, CH₃. F, andCl.

In another embodiment of the present invention, R⁶ is (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl-O—, (C₃₋₆)cycloalkyl-S—, (C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-,phenyl, 5- to 6-membered heteroaryl-O— wherein the heteroaryl contains1, 2, or 3 heteroatoms independently selected from N, O and S, or 5- to6-membered heteroaryl- wherein the heteroaryl contains 1, 2, or 3heteroatoms independently selected from N, O and S, wherein cycloalkyl,phenyl and heteroaryl are unsubstituted or substituted with 1-3substituents selected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy,halo(C₁₋₃)alkoxy, and halogen. In a class of this embodiment of thepresent invention, R⁶ is cyclopropyl, cyclobutyl-O—, cyclobutyl-S—,cyclobutyl-CH₂—, phenyl, thiazolyl-O—, pyridyl-O—, pyrazinyl-O—, orthienyl, wherein cyclopropyl, cyclobutyl, phenyl, thiazolyl, pyridyl,pyrazinyl and thienyl are unsubstituted or substituted with 1-3substituents selected from OCH₃, CHF₂, CH₃, F, and Cl.

In another embodiment of the present invention, R⁶ is halo(C₁₋₃)alkoxy,or halo(C₁₋₃)alkyl, wherein alkyl is unsubstituted or substituted with1-3 substituents selected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl,(C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, and halo. In a class of this embodiment,R⁶ is halo(C₁₋₃)alkoxy, or halo(C₁₋₃)alkyl. In another class of thisembodiment, R⁶ is OCF₃, or CF₃.

In another embodiment of the present invention, R⁶ is(C₃₋₆)cycloalkyl-O—, wherein cycloalkyl is unsubstituted or substitutedwith 1-3 substituents selected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl.(C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, and halogen. In a class of thisembodiment, R⁶ is cyclobutyl-O—, wherein cycloalkyl is unsubstituted orsubstituted with 1-3 substituents selected from OCH₃, CHF₂, CH₃, F, andCl. In another class of this embodiment, R⁶ is cyclobutyl-O—, whereincycloalkyl is unsubstituted or substituted with 1-3 substituentsselected from OCH₃.

In another embodiment of the present invention, R⁶ is

In another embodiment of the present invention, n is 0, 1, 2 or 3. In aclass of this embodiment, n is 1, 2 or 3. In another class of thisembodiment, n is 0, 1, or 2. In another class of this embodiment, n is1, 2 or 3. In another class of this embodiment, n is 0, 1 or 2. Inanother class of this embodiment, n is 1 or 3. In another class of thisembodiment, n is 0. In another class of this embodiment, n is 1. Inanother class of this embodiment, n is 2. In another class of thisembodiment, n is 3.

In another embodiment of the present invention, m is 0 or 1. In a classof this embodiment, m is 0. In another class of this embodiment, m is 1.

In another embodiment of the present invention, p is 0, 1, 2 or 3. In aclass of this embodiment, p is 1, 2 or 3. In another class of thisembodiment, p is 0, 1, or 2. In another class of this embodiment, p is 0or 2. In another class of this embodiment, p is 1 or 2. In another classof this embodiment, p is 0 or 1. In another class of this embodiment, pis 0. In another class of this embodiment, p is 1. In another class ofthis embodiment, p is 2. In another class of this embodiment, p is 3.

In another embodiment of the present invention, q is 0, 1, or 2. In aclass of this embodiment, q is 0 or 1. In another class of thisembodiment, q is 1 or 2. In another class of this embodiment, q is 0 or2. In another class of this embodiment, q is 0. In another class of thisembodiment, q is 1. In another class of this embodiment, q is 2.

In one embodiment, ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl,pyrazolyl, thiazolyl, isoxazolyl, or benzo[d]isoxazolyl. In a class ofthis embodiment, ring A is pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl,isoxazolyl, pyrrolyl, or pyrazolyl, or benzo[d]isoxazolyl. In anotherclass of this embodiment, ring A is pyridinyl, pyrazinyl, thiazolyl,isoxazolyl, pyrrolyl, or pyrazolyl, or benzo[d]isoxazolyl. In anotherclass of this embodiment, ring A is pyridinyl, pyrazinyl, thiazolyl,isoxazolyl, pyrrolyl, or pyrazolyl. In another class of this embodiment,ring A is benzo[d]isoxazolyl. In another class of this embodiment, ringA is phenyl. In another class of this embodiment, ring A is pyrimidinyl.In another class of this embodiment, ring A is pyridinyl. In anotherclass of this embodiment, ring A is pyrazinyl. In another embodiment,ring A is pyrazolyl. In another embodiment, ring A is thiazolyl. Inanother embodiment, ring A is isoxazolyl. In another embodiment, ring Ais benzo[d]isoxazolyl.

In one class of this embodiment, R² is hydrogen.

In one subclass of this class, R¹ is a bond. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₃₋₆)cycloalkyl. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl-. Inone sub-subclass of this subclass, X is a bond. In one sub-subclass ofthis subclass, X is (C₁₋₂)alkyl.

In one class of this embodiment, R² is hydroxy.

In one subclass of this class. R¹ is a bond. In one sub-subclass of thissubclass. X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₃₋₆)cycloalkyl. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl-. Inone sub-subclass of this subclass, X is a bond. In one sub-subclass ofthis subclass, X is (C₁₋₂)alkyl.

In one class of this embodiment, R² is COOH.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is abond.

In one subclass of this class, R¹ is ethyl. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is abond.

In one subclass of this class, R¹ is a bond. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₃₋₆)cycloalkyl. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl-. Inone sub-subclass of this subclass, X is a bond. In one sub-subclass ofthis subclass, X is (C₁₋₂)alkyl.

In one class of this embodiment, R² is hydroxyisoxazole or triazole. Inone class of this embodiment, R² is hydroxyisoxazole. In one class ofthis embodiment, R² is triazole.

In one class of this embodiment, R² is C(O)NH₂, C(O)NHC₁₋₆alkyl,C(O)NHC₃₋₆cycloalkyl, C(O)NHC₂₋₅cycloheteroalkyl, C(O)NH-aryl,C(O)NH-heteroaryl, SO₂C₁₋₆alkyl, SO₂C₃₋₆cycloalkyl,SO₂C₂₋₅cycloheteroalkyl, SO₂-aryl, or SO₂-heteroaryl.

In one subclass of this class, R¹ is a bond. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)cycloalkyl. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one class of this embodiment, R² is C(O)NH₂, C(O)NHC₁₋₆alkyl,C(O)NHcyclopropyl, C(O)NH-cyclobutyl, C(O)NH-cyclopentyl,C(O)NH-cyclohexyl, C(O)NH-oxetane, C(O)NH-tetrahydrofuran,C(O)NH-tetrahydropyran, C(O)NH-pyrrolidine, C(O)NH-piperidine,C(O)NH-phenyl, C(O)NH-thiazole, C(O)NH-oxazole, C(O)NH-imidazole,C(O)NH-furan, C(O)NH-thiophene, C(O)NH-pyridine, C(O)NH-pyrazine,C(O)NH-pyrimidine, SO₂C₁₋₆alkyl SO₂cyclopropyl, SO₂cyclobutyl.SO₂cyclopentyl, SO₂cyclohexyl, SO₂-oxetane, SO₂-tetrahydrofuran,SO₂-tetrahydropyran, SO₂-pyrrolidine, SO₂-piperidine, SO₂-phenyl,SO₂-thiazole, SO₂-oxazole, SO₂-imidazole, SO₂-furan, SO₂-thiophene,SO₂-pyridine, SO₂-pyrazine or SO₂-pyrimidine.

In one subclass of this class, R¹ is a bond. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₃₋₆)cycloalkyl. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl-. Inone sub-subclass of this subclass, X is a bond. In one sub-subclass ofthis subclass, X is (C₁₋₂)alkyl.

In one class of this embodiment, R² is hydrogen, hydroxy, COOH ortetrazole. In one subclass of this embodiment, R² is hydroxy, COOH ortetrazole.

In one subclass of this class, R¹ is a bond. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₃₋₆)cycloalkyl. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl-. Inone sub-subclass of this subclass, X is a bond. In one sub-subclass ofthis subclass, X is (C₁₋₂)alkyl.

In one class of this embodiment, R² is COOH or tetrazole.

In one subclass of this class, R¹ is a bond. In one sub-subclass of thissubclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl. In one sub-subclass ofthis subclass, X is a bond. In one sub-subclass of this subclass, X is(C₁₋₂)alkyl.

In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. In onesub-subclass of this subclass, X is a bond. In one sub-subclass of thissubclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₃₋₆)cycloalkyl. In onesub-subclass of this subclass.

X is a bond. In one sub-subclass of this subclass, X is (C₁₋₂)alkyl.

In one subclass of this class, R¹ is (C₁₋₆)alkyl or —O—(C₁₋₆)alkyl-. Inone sub-subclass of this subclass, X is a bond. In one sub-subclass ofthis subclass, X is (C₁₋₂)alkyl.

In one embodiment, R¹ is a bond.

In one embodiment, R² is hydrogen. In one class of this embodiment, R¹is a bond. In one class of this embodiment, R¹ is (C₁₋₆)alkyl. In oneclass of this embodiment, R¹ is —O—(C₁₋₆)alkyl-. In one class of thisembodiment, R¹ is (C₃₋₆)cycloalkyl.

In one embodiment, R² is hydroxy. In one class of this embodiment, R¹ isa bond. In one class of this embodiment, R¹ is (C₁₋₆)alkyl. In one classof this embodiment, R¹ is —O—(C₁₋₆)alkyl-. In one class of thisembodiment, R¹ is (C₃₋₆)cycloalkyl.

In one embodiment, R² is COOH. In one class of this embodiment, R¹ is abond. In one class of this embodiment, R¹ is (C₁₋₆)alkyl. In one classof this embodiment, R¹ is —O—(C₁₋₆)alkyl-. In one class of thisembodiment, R¹ is (C₃₋₆)cycloalkyl.

In one class of this embodiment, R² is hydroxyisoxazole or triazole. Inone class of this embodiment, R² is hydroxyisoxazole. In one class ofthis embodiment, R² is triazole.

In one class of this embodiment, R² is tetrazolyl. In one subclass ofthis class, R¹ is a bond. In one subclass of this class. R¹ is(C₁₋₆)alkyl. In one subclass of this class, R¹ is —O—(C₁₋₆)alkyl-. Inone subclass of this class, R¹ is (C₃₋₆)cycloalkyl.

In one embodiment, R² is hydrogen, hydroxy. COOH, or tetrazolyl. In oneclass of this embodiment, R¹ is a bond,

In one embodiment, X is bond, (C₁₋₂)alkyl, or halo(C1-2)alkyl. In oneembodiment, X is bond, or CH₂.

In one embodiment, R¹ is hydrogen, hydroxy, COOH, or tetrazole. In oneembodiment, R² is hydroxy. COOH, or tetrazole. In one embodiment, R² isCOOH, or tetrazole. In one embodiment, R² is COOH. In one embodiment, R²is tetrazole.

In one embodiment, R³ is hydrogen, halo, cyano, or (C₁₋₃)alkyl. In oneembodiment, R³ is hydrogen, fluoro, chloro, or methyl. In one class ofthis embodiment, R³ is hydrogen. In one class of this embodiment, R³ isfluoro. In one class of this embodiment, R³ is chloro. In one class ofthis embodiment, R³ is fluoro or chloro. In one class of thisembodiment, R³ is methyl.

In one embodiment, R³ is hydrogen, F or CH₃.

In one embodiment R⁴ is hydrogen, (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, or halo.In one embodiment R⁴ is hydrogen, or R⁴ is (C₁₋₃)alkyl. In oneembodiment R⁴ is hydrogen, or CH₃. In one embodiment, R⁴ is hydrogen. Inone embodiment, R⁴ is (C₁₋₃)alkyl. In one embodiment, R⁴ ishalo(C₁₋₃)alkyl. In one embodiment, R⁴ is halo. In one embodiment, R⁴ ishydrogen, fluoro, or methyl. In one embodiment R⁴ is hydrogen.

In one embodiment, R⁵ is cyano, (C₁₋₃)alkyl, halo(C₁₋₃)alkyl,(C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, or halo. In one embodiment, R⁵ is —CN,—CH₃, —CF₃, —CHF₂, —OCH₃, —OCF₃, Cl, or F. In one embodiment, R⁵ ismethoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, methyl, orcyano. In one embodiment, R⁵ is cyano, (C₁₋₃)alkyl, halo(C₁₋₃)alkyl,(C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, or halo. In one embodiment, R⁵ is —CN,—CH₃, —OCH₃, Cl, or F.

In one embodiment, R⁶ is

In one embodiment, R⁶ is

In one embodiment,

In one embodiment,

In one embodiment,

In one embodiment,

In one embodiment,

and n is 0, or 1.

In one embodiment,

and n is 0, or 1.

In another embodiment of the present invention, the invention relates tocompounds of structural formula I:

wherein:

X is

-   -   (1) a bond, or    -   (2) (C₁₋₂)alkyl:        ring A is    -   (1) aryl,    -   (2) 5- or 6-membered heteroaryl containing 1, 2, or 3        heteroatoms independently selected from N, O and S, or    -   (3) 9- or 10-membered fused heteroaryl containing 1, 2, or 3        heteroatoms independently selected from N, O, and S:

R¹ is

-   -   (1) bond,    -   (2) (C₁₋₆)alkyl,    -   (3) —O—(C₁₋₆)alkyl-, or    -   (4) (C₃₋₆)cycloalkyl;

R² is

-   -   (1) hydrogen,    -   (2) hydroxy,    -   (3) COOH, or    -   (4) tetrazole;

R³ is

-   -   (1) hydrogen,    -   (2) halogen, or    -   (3) (C₁₋₃)alkyl;

R⁴ is

-   -   (1) hydrogen, or    -   (2) (C₁₋₃)alkyl:

R¹ is

-   -   (1) cyano,    -   (2) (C₁₋₃)alkyl,    -   (3) halo(C₁₋₃)alkyl,    -   (4) (C₁₋₃)alkoxy, or    -   (5) halogen;

R⁶ is

-   -   (1) halo(C₁₋₃)alkoxy,    -   (2) halo(C₁₋₃)alkyl,    -   (3) (C₃₋₆)cycloalkyl,    -   (4) (C₃₋₆)cycloalkyl-O—,    -   (5) (C₃₋₆)cycloalkyl-S—,    -   (6) (C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-,    -   (7) phenyl,    -   (8) 5- to 6-membered heteroaryl-O— wherein the heteroaryl        contains 1, 2, or 3 heteroatoms independently selected from N, O        and S, or    -   (9) 5- to 6-membered heteroaryl- wherein the heteroaryl contains        1, 2, or 3 heteroatoms independently selected from N, O and S,        wherein alkyl, cycloalkyl, phenyl and heteroaryl are        unsubstituted or substituted with 1-3 substituents selected from        (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy,        and halogen;        or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula I

wherein:X is a bond;ring A is aryl;R¹ is (C₁₋₆)alkyl;

R² is COOH, R³ is

-   -   (1) hydrogen, or    -   (2) halogen;        R⁴ is hydrogen;

R⁵ is

-   -   (1) cyano, or    -   (2) halogen;        R⁶ is (C₃₋₆)cycloalkyl-O—, wherein cycloalkyl is unsubstituted        or substituted with 1-3 substituents selected from (C₁₋₃)alkyl,        halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, and halogen:        or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention relates to compounds of formula I-A:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵, R⁶and n are as previously defined. In one class of this embodiment, R³,and R⁴ are each hydrogen.

In one embodiment, the invention relates to compounds of formula I-B:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵, R⁶and n are as previously defined. In one class of this embodiment, R³,and R⁴ are each hydrogen.

In one embodiment, the invention relates to compounds of formula I-C:

or a pharmaceutically acceptable salt thereof, wherein R⁶ is phenylunsubstituted or substituted with (C₁₋₃)alkyl, (C₁₋₃)alkoxy, or halo;and n is 0, 1 or 2; and R³, R⁴, R⁵ are as previously defined. In oneclass of this embodiment, R³, and R⁴ are each hydrogen.

In one embodiment, the invention relates to compounds of formula I-D:

or a pharmaceutically acceptable salt thereof, wherein R⁶ is phenylunsubstituted or substituted with (C₁₋₃)alkyl, (C₁₋₃)alkoxy, or halo;and n is 0 or 1; and R³, R⁴, R⁵ are as previously defined. In one classof this embodiment, R³, and R⁴ are each hydrogen.

In one embodiment, the invention relates to compounds of formula I-E:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵, R⁶and n are as previously defined. In one class of this embodiment, R³,and R⁴ are each hydrogen.

In one embodiment, the invention relates to compounds of formula I-F:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵, R⁶and n are as previously defined. In one class of this embodiment, R³,and R⁴ are each hydrogen.

In one embodiment, the invention relates to compounds of formula I-G:

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, R⁵, R⁶and n are as previously defined. In one class of this embodiment, R³,and R⁴ are each hydrogen.

In the compounds of formulas I, I-A, I-B, I-C, I-D, I-E, I-F, and I-G,the R⁴ substituent is substituted on the piperidine ring of the1,2,3,4-tetrahydroisoquinoline ring, and the R³ substituent issubstituted on the phenyl of the 1,2,3,4-tetrahydroisoquinoline ring, asshown below:

The present invention also relates to a GPR120 function regulating agentcontaining a compound represented by formulas I to I-G or apharmaceutically acceptable salt thereof as an active ingredient.Particularly, the present invention relates to a GPR120 agonistcontaining a compound represented by formulas I to I-G or apharmaceutically acceptable salt thereof as an active ingredient.

The present invention also relates to an agent for treating and/orpreventing diabetes, obesity, hyperlipidemia. NASH, or an inflammationrelated disorder, containing a compound represented by formulas I to I-Gor a pharmaceutically acceptable salt thereof, as an active ingredient.

Furthermore, the present invention relates to a pharmaceuticalcomposition containing the compound represented by formulas I to I-G anda pharmaceutically acceptable carrier.

The present also relates a compound represented by formulas I to 1-G foruse as a medicament.

The present invention relates to the use of a compound represented byformulas I to I-G or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in treating a condition selectedfrom the group consisting of diabetes, hyperlipidemia, obesity, NASH,and inflammation related disorders.

The present invention relates to the treatment of a condition selectedfrom the group consisting of diabetes, hyperlipidemia, obesity, NASH,and inflammation related disorders comprising administering to anindividual in need of such treatment a pharmaceutical compositioncomprising the compound represented by formulas I to I-G.

A compound according to an embodiment of the present invention or thepharmaceutically acceptable salt thereof has a strong GPR120 functionregulating action, particularly an agonist action, and may be useful fortreating and/or preventing diabetes, obesity, hyperlipidemia, NASH, oran inflammation related disorder.

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, and the like, means carbon chains which may be linear orbranched, or combinations thereof, containing the indicated number ofcarbon atoms. If no number is specified, 1-6 carbon atoms are intendedfor linear and 3-7 carbon atoms for branched alkyl groups. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

“Alkoxy” refers to an alkyl group linked to oxygen.

“Aryl” refers to phenyl or naphthyl.

“Halo” is halogen; halo and halogen include fluorine, chlorine, bromineand iodine.

“Cycloalkyl” means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated if no number of atoms is specified,3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that arefused. “Cycloalkyl” also includes monocyclic rings fused to an arylgroup in which the point of attachment is on the non-aromatic portion.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyland the like.

“Haloalkyl” include mono-substituted as well as multiple halosubstituted alkyl groups, up to perhalo substituted alkyl. For example,trifluoromethyl is included.

“Haloalkoxy” and “haloalkyl-O” are used interchangeably and refer tohalo substituted alkyl groups linked through the oxygen atom. Haloalkoxyinclude mono-halo substituted alkoxy groups as well alkoxy groupssubstituted with multiple halo substituents, up to perhalo substitutedalkoxy. For example, trifluoromethoxy is included.

“Heterocyclyl”, “heterocycle”, “heterocyclic” or “cycloheteroalkyl”refers to nonaromatic cyclic ring structures in which one or more atomsin the ring, the heteroatom(s), is an element other than carbon.Heteroatoms are typically O, S or N atoms. Examples of heterocyclylgroups include: piperidine, piperazine, morpholine, pyrrolidine,tetrahydrofuran, azetidine, oxirane, or aziridine, and the like.

“Heteroaryl” refers to aromatic cyclic ring structures in which one ormore atoms in the ring, the heteroatoms(s), is an element other thancarbon. Heteroatoms are typically O, S, or N atoms. Examples ofheteroaryl groups include: pyridine, pyrimidinyl, pyrrole, pyridazine,isoxazole, indole, or imidazole.

“Fused heteroaryl” refers to a heteroaryl group fused to an aryl orheteroaryl group. Examples of fused heteroaryl groups includebenzo[d]oxazolyl, or benzo[d]isoxazolyl.

In the compounds described herein, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the formulasdescribed herein. For example, different isotopic forms of hydrogen (H)include protium (1H) and deuterium (2H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within the formulas described herein canbe prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

The individual tautomers of the compounds of the formulas describedherein, as well as mixture thereof, are encompassed with compounds ofthe formulas described herein. Tautomers are defined as compounds thatundergo rapid proton shifts from one atom of the compound to anotheratom of the compound. Some of the compounds described herein may existas tautomers with different points of attachment of hydrogen. Such anexample may be a ketone and its enol form known as keto-enol tautomers.

Compounds of the formulas described herein may be separated intodiastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent. The pair of enantiomers thusobtained may be separated into individual stereoisomers by conventionalmeans, for example by the use of an optically active amine or acid as aresolving agent or on a chiral HPLC column.

Alternatively, any enantiomer of a compound of the formulas describedherein may be obtained by stereospecific synthesis using optically purestarting materials or reagents of known configuration.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Compounds described herein may contain an asymmetric center and may thusexist as enantiomers. Where the compounds according to the inventionpossess two or more asymmetric centers, they may additionally exist asdiastereomers. When bonds to the chiral carbon are depicted as straightlines in the formulas of the invention, it is understood that both the(R) and (S) configurations of the chiral carbon, and hence bothenantiomers and mixtures thereof, are embraced within the formulas. Thepresent invention includes all such possible stereoisomers assubstantially pure resolved enantiomers, racemic mixtures thereof, aswell as mixtures of diastereomers. Except where otherwise specified, theformulae encompassing compounds of the present invention are shownwithout a definitive stereochemistry at certain positions. The presentinvention therefore may be understood to include all stereoisomers ofcompounds of formulas I to I-G and pharmaceutically acceptable saltsthereof.

Diastereoisomeric pairs of enantiomers may be separated by, for example,fractional crystallization from a suitable solvent, and the pair ofenantiomers thus obtained may be separated into individual stereoisomersby conventional means, for example by the use of an optically activeacid or base as a resolving agent or on a chiral HPLC column. Further,any enantiomer or diastereomer of a compound of formulas I to I-G may beobtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

Furthermore, the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Solvates, and in particular, the hydrates of the compounds ofthe structural formulas described herein are also included in thepresent invention.

Compounds of the present invention are potent agonists of the GPR120receptor. These compounds and pharmaceutically acceptable salts thereofare modulators of the receptor known as GPR120, and are therefore usefulin the treatment of diseases that are modulated by GPR120 ligands andagonists. Many of these diseases are summarized below. Said compoundsmay be used for the manufacture of a medicament for treating one or moreof diseases or conditions, including, without limitation:

-   -   (1) noninsulin dependent diabetes mellitus (type 2 diabetes);    -   (2) hyperglycemia;    -   (3) metabolic syndrome/syndrome X;    -   (4) obesity;    -   (5) ischemia and myocardial infarction;    -   (6) neurological disorders such as Alzheimer's disease,        schizophrenia, and impaired cognition;    -   (7) hypercholesterolemia;    -   (8) hypertriglyceridemia (elevated levels of        triglyceride-rich-lipoproteins);    -   (9) mixed or diabetic dyslipidemia;    -   (10) low HDL cholesterol;    -   (11) high LDL cholesterol;    -   (12) Hyperapobetalipoproteinemia;    -   (13) atherosclerosis;    -   (14) inflammation related disorders;    -   (15) type 1 diabetes;    -   (16) insulin resistance;    -   (17) fatty liver; and    -   (18) non-alcoholic steatohepatitis (NASH).

Because the compounds are agonists of the GPR120 receptor, the compoundsmay be useful for lowering glucose, lipids, and insulin resistance andincreasing insulin sensitivity in diabetic patients and in non-diabeticpatients who have impaired glucose tolerance and/or are in apre-diabetic condition. The compounds may be useful to amelioratehyperinsulinemia, which often occurs in diabetic or pre-diabeticpatients, by modulating the swings in the level of serum glucose thatoften occurs in these patients. The compounds may be useful for treatingor reducing insulin resistance. The compounds may be useful forincreasing insulin sensitivity. The compounds are useful for treating orpreventing gestational diabetes.

Additionally, by keeping hyperglycemia under control, the compounds maybe useful to delay or for preventing vascular restenosis and diabeticretinopathy.

The compounds of this invention may be useful in improving or restoringβ-cell function, so that they may be useful in treating type 1 diabetesor in delaying or preventing a patient with type 2 diabetes from needinginsulin therapy.

The compounds of this invention may be useful in treating inflammationrelated disorders such as obesity, diabetes, NASH, cancer, andcardiovascular disease.

The compounds, compositions, and medicaments as described herein may befurther useful for reducing the risks of adverse sequelae associatedwith metabolic syndrome, or Syndrome X, and in reducing the risk ofdeveloping atherosclerosis, delaying the onset of atherosclerosis,and/or reducing the risk of sequelae of atherosclerosis. Sequelae ofatherosclerosis include angina, claudication, heart attack, stroke, andothers.

The compounds may be useful for reducing appetite and body weight inobese subjects and may therefore be useful in reducing the risk ofco-morbidities associated with obesity such as hypertension,atherosclerosis, diabetes, and dyslipidemia.

By elevating levels of active GLP-1 in vivo, the compounds are useful intreating neurological disorders such as Alzheimer's disease, multiplesclerosis, and schizophrenia.

One aspect of the invention provides a method for the treatment andcontrol of mixed or diabetic dyslipidemia, hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, NASH,and/or hypertriglyceridemia, which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound of the formulas described herein or a pharmaceuticallyacceptable salt thereof. The compound may be used alone oradvantageously may be administered with a cholesterol biosynthesisinhibitor, particularly an HMG-CoA reductase inhibitor (e.g.,simvastatin, atorvastatin, rosuvastatin and the like). The compound mayalso be used advantageously in combination with other lipid loweringdrugs such as cholesterol absorption inhibitors (e.g., stanol esters,sterol glycosides or azetidinones such as ezetimibe), ACAT inhibitors(e.g., avasimibe), CETP inhibitors (e.g. anacetrapib), niacin, bile acidsequestrants, microsomal triglyceride transport inhibitors, and bileacid reuptake inhibitors. Such combination treatments are useful for thetreatment or control of conditions such hypercholesterolemia,atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia,high LDL, and low HDL.

Another aspect of the invention provides a method for the treatment andcontrol of obesity or metabolic syndrome, which comprises administeringto a patient in need of such treatment a therapeutically effectiveamount of a compound having the formulas described herein or apharmaceutically acceptable salt thereof. The compound may be used aloneor advantageously may be administered with an anti-obesity agent, suchas a lipase inhibitor (e.g., orlistat) or a monoamine neurotransmitteruptake inhibitor (e.g., sibutramine or phentermine). The compound mayalso be used advantageously in combination with CB-1 inverse agonists orantagonists (e.g., rimonabant).

The present invention further relates to a method of treatinghyperglycemia, diabetes or insulin resistance in a mammalian patient inneed of such treatment which comprises administering to said patient acompound in accordance with the formulas described herein or apharmaceutically acceptable salt thereof in an amount that is effectiveto treat hyperglycemia, diabetes or insulin resistance.

Yet another aspect of the invention that is of interest relates to amethod of treating atherosclerosis in a mammalian patient in need ofsuch treatment, comprising administering to said patient a compound inaccordance with a compound in accordance with the formulas describedherein or a pharmaceutically acceptable salt thereof in an amount thatis effective to treat atherosclerosis.

Yet another aspect of the invention that is of interest relates to amethod of delaying the onset of one of the aforementioned conditions anddisorders where insulin resistance is a component in a mammalian patientin need thereof, comprising administering to the patient a compound inaccordance with the formulas described herein or a pharmaceuticallyacceptable salt thereof in an amount that is effective to delay theonset of said condition.

Yet another aspect of the invention that is of interest relates to amethod of reducing the risk of developing one of the aforementionedconditions and disorders where insulin resistance is a component in amammalian patient in need thereof, comprising administering to thepatient a compound in accordance with the formulas described herein or apharmaceutically acceptable salt thereof in an amount that is effectiveto reduce the risk of developing said condition.

Yet another aspect of the invention that is of interest relates to amethod of treating a condition or reducing the risk of developing acondition or delaying the onset of a condition selected from the groupconsisting of (1) hyperglycemia, (2) impaired glucose tolerance, (3)insulin resistance, (4) obesity. (5) lipid disorders, (6) dyslipidemia,(7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia,(10) low HDL levels, (11) high LDL levels. (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominalobesity, (16) neurodegenerative disease, (17) retinopathy, (18)nephropathy, (19) neuropathy, (20) Syndrome X, (21) hypertension, (22)fatty liver, (23) non-alcoholic steatohepatitis (NASH) and otherconditions and disorders where insulin resistance is a component, in amammalian patient in need of such treatment, comprising administering tothe patient a compound in accordance with the formulas described hereinor a pharmaceutically acceptable salt thereof in an amount that iseffective to treat said condition, and a compound selected from thegroup consisting of:

(a) DPP-IV inhibitors (e.g., sitagliptin, alogliptin, omarigliptin,linagliptin, vildagliptin, trelagliptin);

(b) insulin sensitizers selected from the group consisting of (i) PPARagonists and (ii) biguanides;

(c) insulin and insulin mimetics (e.g., insulin degludec, insulinglargine, insulin lispro);

(d) sulfonylureas and other insulin secretagogues;

(e) α-glucosidase inhibitors;

(f) glucagon receptor antagonists;

(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists (e.g.,dulaglutide, exenatide, semaglutide, albiglutide, liraglutide,lixisenatide, taspoglutide);

(h) GIP, GIP mimetics, and GIP receptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

(j) cholesterol lowering agents selected from the group consisting of

(i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinylalcohol, nicotinic acid and salts thereof. (iv) PPARα agonists, (v) PPARα/γdual agonists (e.g., aleglitazar), (vi) inhibitors of cholesterolabsorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and(viii) anti-oxidants;

(k) PPARδ agonists;

(l) SGLT inhibitors (e.g., empagliflozin, dapagliflozin, canagliflozin,BI-10773, tofogliflozin, ipragliflozin, LX-4211, PF-4971729,remogloflozin, TS-071, ertugliflozin);

(m) antiobesity compounds;

(n) ileal bile acid transporter inhibitors;

(o) anti-inflammatory agents excluding glucocorticoids:

(p) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(q) antihypertensives including those acting on the angiotensin or reninsystems, such as angiotensin converting enzyme inhibitors, angiotensinII receptor antagonists or renin inhibitors, (e.g., lisinopril,losartan); and

(r) GPR-40 agonists;

said compounds being administered to the patient in an amount that iseffective to treat said condition.

For dosing purposes, any suitable route of administration may beemployed for providing a mammal, especially a human, with an effectiveamount of a compound of the present invention. Dosage forms may includetablets, troches, dispersions, suspensions, solutions, capsules, creams,ointments, aerosols, and the like. Most preferably, compounds of theformulas described herein or a pharmaceutically acceptable salt thereofare administered orally. The effective dosage of active ingredientemployed may vary depending on the particular compound employed, themode of administration, the condition being treated and the severity ofthe condition being treated. Such dosage may be ascertained readily by aperson skilled in the art.

When treating or controlling diabetes mellitus or other diseases forwhich compounds of the formulas described herein are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.1milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. For most large mammals, thetotal daily dosage is from about 1.0 milligrams to about 1000milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 1 milligram to about 350 milligrams. For aparticularly potent compound, the dosage for an adult human may be aslow as 0.1 mg. The dosage regimen may be adjusted within this range oreven outside of this range to provide the optimal therapeutic response.Oral administration will usually be carried out using tablets orcapsules. Examples of doses in tablets and capsules are 0.1 mg, 0.25 mg,0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg,5.5 mg, 6 g, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 12mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, 700 mg,750 mg, 800 mg and 1000 mg. Other oral forms may also have the same orsimilar dosages.

Another aspect of the invention that is of interest is a pharmaceuticalcomposition comprised of a compound of the formulas described herein ora pharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of the formulas describedherein or a pharmaceutically acceptable salt as an active ingredient, aswell as a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients. The term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicbases or acids including inorganic bases or acids and organic bases oracids.

Salts of basic compounds encompassed within the term “pharmaceuticallyacceptable salt” refer to non-toxic salts of the compounds describedherein which are generally prepared by reacting the free base with asuitable organic or inorganic acid. Representative salts of basiccompounds described herein include, but are not limited to, thefollowing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, camsylate, carbonate, chloride,clavulanate, citrate, edetate, edisylate, estolate, esylate, formate,fumarate, gluceptate, gluconate, glutamate, hexylresorcinate,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate(embonate), pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Furthermore, where thecompounds described herein carry an acidic moiety, suitablepharmaceutically acceptable salts thereof include, but are not limitedto, salts derived from inorganic bases including aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,mangamous, potassium, sodium, zinc, and the like. Particularly preferredare the ammonium, calcium, magnesium, potassium, and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, cyclic amines, andbasic ion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine.N-ethylmorpholine. N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine, and thelike.

A pharmaceutical composition may also comprise a prodrug, or apharmaceutically acceptable salt thereof, if a prodrug is administered.

The compositions are typically suitable for oral, rectal, topical,parenteral (including subcutaneous, intramuscular, and intravenous),ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the condition being treated and onthe particular active ingredient selected. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art.

In practical use, compounds of the formulas described herein, or thepharmaceutically acceptable salts thereof can be combined as the activeingredient in intimate admixture with the pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage form. Solid pharmaceutical carriersare therefore typically employed. If desired, tablets may be coated bystandard aqueous or nonaqueous techniques. Such compositions andpreparations typically comprise at least about 0.1 percent of activecompound, the remainder of the composition being the carrier. Thepercentage of active compound in these compositions may, of course, bevaried and is conveniently between about 2 percent to about 60 percentof the weight of the dosage form. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be delivered.

Alternatively, the active compound can be administered intranasally as,for example, in the form of liquid drops or a spray.

The tablets, capsules and the like also typically contain a binder.Examples of suitable binders include gum tragacanth, acacia, gelatin anda synthetic or semisynthetic starch derivative, such ashydroxypropylmethylcellulose (HPMC); excipients such as dicalciumphosphate; a disintegrating agent such as corn starch, potato starch,alginic acid; a lubricant such as magnesium stearate; and in someinstances, a sweetening agent such as sucrose, lactose or saccharin.When the dosage form employed is a capsule, it may contain, in additionto the components described above, a liquid carrier such as fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. Syrups and elixirs typically contain, inaddition to the active ingredient, sucrose as a sweetening agent, methylor propylparabens as a preservative, a dye and a flavoring such ascherry or orange flavor.

The compound of the formulas described herein or a pharmaceuticallyacceptable salt thereof may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in water,saline or another biocompatible vehicle, suitably mixed with asurfactant, buffer, and the like. Dispersions can also be prepared inglycerol, liquid polyethylene glycols and mixtures thereof in an oil.Under ordinary conditions of storage and use, these preparations canalso contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions and dispersions, and sterile powders for theextemporaneous preparation of sterile injectable solutions anddispersions. The preparation should be prepared under sterile conditionsand be fluid to the extent that easy syringability exists. It should besufficiently stable under the conditions of manufacture and storage andpreserved against the growth of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g. glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and suitableoils.

Combination Therapy

The compounds of the present invention are further useful in methods forthe prevention or treatment of the aforementioned diseases, disordersand conditions in combination with other therapeutic agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of formulas Ito I-G or the other drugs may have utility, where the combination of thedrugs together are safer or more effective than either drug alone. Suchother drug(s) may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound offormulas I to I-G When a compound of formulas I to I-G is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of formulas I to I-G is preferred. However, the combinationtherapy may also include therapies in which the compound of formulas Ito I-G and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compounds ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof formulas I to I-G.

Examples of other active ingredients that may be administered separatelyor in the same pharmaceutical composition in combination with a compoundof the formulas described herein include, but are not limited to:

(1) dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin,alogliptin, omarigliptin, linagliptin, vildagliptin, trelagliptin);

(2) insulin sensitizers, including (i) PPARγ agonists, such as theglitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and otherPPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1,GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, andnaveglitazar); (2) PPARα agonists such as fenofibric acid derivatives(e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate),(3) selective PPARγ modulators (SPPARγM's), (e.g., such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™;and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g.,ISIS-113715 and TTP814):

(3) insulin or insulin analogs (e.g., insulin detemir, insulinglulisine, insulin degludec, insulin glargine, insulin lispro andinhalable formulations of each);

(4) leptin and leptin derivatives and agonists;

(5) amylin and amylin analogs (e.g., pramlintide);

(6) sulfonylurea and non-sulfonylurea insulin secretagogues (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide,meglitinides, nateglinide and repaglinide):

(7) α-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol);

(8) glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021and KT6-971);

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, andmimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide,albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide,CJC-131, and BIM-51077, including intranasal, transdermal, andonce-weekly formulations thereof);

(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (e.g., simvastatin, lovastatin, pravastatin, cerivastatin,fluvastatin, atorvastatin, pitavastatin and rosuvastatin), (ii) bileacid sequestering agents (e.g., colestilan, colestimide, colesevalamhydrochloride, colestipol, cholestyramine, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) inhibitors of cholesterolabsorption, (e.g., ezetimibe), and (iv) acyl CoA:cholesterolacyltransferase inhibitors, (e.g., avasimibe);

(11) HDL-raising drugs, (e.g., niacin and nicotinic acid receptoragonists, and extended-release versions thereof);

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such asaspirin, non-steroidal anti-inflammatory drugs or NSAIDs,glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;

(14) antihypertensive agents, such as ACE inhibitors (e.g., lisinopril,enalapril, ramipril, captopril, quinapril, and tandolapril), A-IIreceptor blockers (e.g., losartan, candesartan, irbesartan, olmesartanmedoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors(e.g., aliskiren), beta blockers, and calcium channel blockers:

(15) glucokinase activators (GKAs) (e.g., AZD6370);

(16) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, (e.g., suchas those disclosed in U.S. Pat. No. 6,730,690, and LY-2523199);

(17) CETP inhibitors (e.g., anacetrapib, and torcetrapib):

(18) inhibitors of fructose 1,6-bisphosphatase, (e.g., such as thosedisclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782;and 6,489,476);

(19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2):

(20) AMP-activated Protein Kinase (AMPK) activators;

(21) other agonists of the G-protein-coupled receptors: (i) GPR-109,(ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g.,TAK875):

(22) SSTR3 antagonists (e.g., such as those disclosed in WO2009/001836);

(23) neuromedin U receptor agonists (e.g., such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS)):

(24) SCD inhibitors;

(25) GPR-105 antagonists (e.g., such as those disclosed in WO2009/000087):

(26) SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin,dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin,TS-071, tofogliflozin, ipragliflozin, ertugliflozin, and LX-4211);

(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and2 (DGAT-1 and DGAT-2);

(28) inhibitors of fatty acid synthase;

(29) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1and 2 (MGAT-1 and MGAT-2);

(30) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19,GPR131, and M-BAR);

(31) ileal bile acid transporter inhibitors;

(32) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

(33) PPAR agonists;

(34) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(35) IL-1b antibodies, (e.g., XOMA052 and canakinumab); and

(36) bromocriptine mesylate and rapid-release formulations thereof.

Of particular interest are dipeptidyl peptidase-IV (DPP-4) inhibitorsthat can be used in combination with compounds of the present invention.Such inhibitors include, without limitation, sitagliptin (disclosed inU.S. Pat. No. 6,699,871), omarigliptin, SYR-472, teneligliptin, KRP104,TS021, AMG222, SK0403, LC15-0444, vildagliptin, saxagliptin, alogliptin,melogliptin, linagliptin, and pharmaceutically acceptable salts thereof,and fixed-dose combinations of these compounds with metforminhydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin,rosuvastatin, ertugliflozin, ipragliflozin, or a sulfonylurea.

Antiobesity compounds that can be combined with compounds of formulas Ito I-G include topiramate; zonisamide; naltrexone; phentermine;bupropion; the combination of bupropion and naltrexone; the combinationof bupropion and zonisamide; the combination of topiramate andphentermine; fenfluramine; dexfenfluramine; sibutramine; lipaseinhibitors, such as orlistat and cetilistat; melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists; CCK-1agonists; melanin-concentrating hormone (MCH) receptor antagonists;neuropeptide Y₁ or Y₅ antagonists (such as MK-0557); CB1 receptorinverse agonists and antagonists (such as rimonabant and taranabant); β₃adrenergic receptor agonists; ghrelin antagonists; bombesin receptoragonists (such as bombesin receptor subtype-3 agonists); and5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For areview of anti-obesity compounds that can be combined with compounds ofthe present invention, see S. Chaki et al., “Recent advances in feedingsuppressing agents: potential therapeutic strategy for the treatment ofobesity,” Expert Opin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswickand K. Lee, “Emerging antiobesity drugs,” Expert Opin. Emerging Drugs,8: 217-237 (2003); J. A. Femandez-Lopez, et al., “PharmacologicalApproaches for the Treatment of Obesity,” Drugs, 62: 915-944 (2002); andK. M. Gadde, et al., “Combination pharmaceutical therapies for obesity,”Exp. Opin. Pharmacother., 10: 921-925 (2009).

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises one or more of the following agents:

(a) a compound of structural formulas I to I-G;

(b) one or more compounds selected from the group consisting of:

-   -   (1) dipeptidyl peptidase-IV (DPP-4) inhibitors;    -   (2) insulin sensitizers, including (i) PPARγ agonists, such as        the glitazones (e.g. AMG 131, MBX2044, mitoglitazone,        lobeglitazone, IDR-105, pioglitazone, rosiglitazone, and        balaglitazone) and other PPAR ligands, including (1) PPARα/γ        dual agonists, such as ZYH1, YYH2, chiglitazar, GFT505,        muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2)        PPARα agonists, such as fenofibric acid derivatives (e.g.,        gemfibrozil, clofibrate, ciprofibrate, fenofibrate and        bezafibrate), (3) selective PPARγ modulators (SPPARγM's),        and (4) PPARγ partial agonists; (ii) biguanides, such as        metformin and its pharmaceutically acceptable salts, in        particular, metformin hydrochloride, and extended-release        formulations thereof, such as Glumetza®), Fortamet®, and        GlucophageXR®; (iii) protein tyrosine phosphatase-1B (PTP-1B)        inhibitors, such as ISI-113715, and TTP814;    -   (3) sulfonylurea and non-sulfonylurea insulin secretagogues,        (e.g., tolbutamide, glyburide, glipizide, glimepiride,        mitiglinide, and meglitinides, such as nateglinide and        repaglinide);    -   (4) α-glucosidase inhibitors (e.g., acarbose, voglibose and        miglitol);    -   (5) glucagon receptor antagonists;    -   (6) LDL cholesterol lowering agents such as (i) HMG-CoA        reductase inhibitors (e.g., lovastatin, simvastatin,        pravastatin, cerivastatin, fluvastatin, atorvastatin,        pitavastatin, and rosuvastatin), (ii) bile acid sequestering        agents (e.g., colestilan, cholestyramine, colestimide,        colesevelam hydrochloride, colestipol, and dialkylaminoalkyl        derivatives of a cross-linked dextran), (iii) inhibitors of        cholesterol absorption, (e.g., ezetimibe), and (iv) acyl        CoA:cholesterol acyltransferase inhibitors (e.g., avasimibe):

(7) HDL-raising drugs, such as niacin or a salt thereof andextended-release versions thereof:

(8) antiobesity compounds;

-   -   (9) agents intended for use in inflammatory conditions, such as        aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),        glucocorticoids, and selective cyclooxygenase-2 (COX-2)        inhibitors;    -   (10) antihypertensive agents, such as ACE inhibitors (e.g.,        enalapril, lisinopril, ramipril, captopril, quinapril, and        tandolapril), A-II receptor blockers (e.g., losartan,        candesartan, irbesartan, olmesartan medoxomil, valsartan,        telmisartan, and eprosartan), renin inhibitors (e.g.,        aliskiren), beta blockers (e.g., calcium channel blockers);    -   (11) glucokinase activators (GKAs) (e.g., AZD6370);    -   (12) inhibitors of 11β-hydroxysteroid dehydrogenase type 1        (e.g., such as those disclosed in U.S. Pat. No. 6,730,690; WO        03/104207; and WO 04/058741);    -   (13) inhibitors of cholesteryl ester transfer protein (CETP),        (e.g., torcetrapib and anacetripib);    -   (14) inhibitors of fructose 1,6-bisphosphatase (e.g., such as        those disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903;        6,284,748; 6,399,782; and 6,489,476);    -   (15) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);    -   (16) AMP-activated Protein Kinase (AMPK) activators;    -   (17) agonists of the G-protein-coupled receptors: (i)        GPR-109, (ii) GPR-119 (e.g., MBX2982, and PSN821), and (iii)        GPR-40;    -   (18) SSTR3 antagonists (e.g., such as those disclosed in WO        2009/011836);    -   (19) neuromedin U receptor agonists (e.g., such as those        disclosed in WO2009/042053, including, but not limited to,        neuromedin S (NMS));    -   (20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);    -   (21) GPR-105 antagonists (e.g., such as those disclosed in WO        2009/000087);    -   (22) inhibitors of glucose uptake, such as sodium-glucose        transporter (SGLT) inhibitors and its various isoforms, such as        SGLT-1; SGLT-2 (e.g., ASP1941, TS071, BI10773, tofogliflozin,        LX4211, canagliflozin, dapagliflozin, ertugliflozin,        ipragliflozin and remogliflozin; and SGLT-3);    -   (23) inhibitors of acyl coenzyme A:diacylglycerol        acyltransferase 1 and 2 (DGAT-1 and DGAT-2);    -   (24) inhibitors of fatty acid synthase;    -   (25) inhibitors of acyl coenzyme A:monoacylglycerol        acyltransferase 1 and 2 (MGAT-1 and MGAT-2);    -   (26) agonists of the TGR5 receptor (also known as GPBAR1, BG37,        GPCR19, GPR131, and M-BAR);    -   (28) bromocriptine mesylate and rapid-release formulations        thereof, and    -   (29) IL-1b antibodies (e.g., XOMA052, and canakinumab); and

(c) a pharmaceutically acceptable carrier.

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention may beemployed. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Abbreviations

The following abbreviations may be used in the synthetic schemes orExamples: ACN is acetonitrile; AcOH is acetic acid; Ac₂O is aceticanhydride; anhyd. or anhydr. is anhydrous; aq. is aqueous; Ar is aryl;BINAP is (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); (BOC)₂O is Bocanhydride or di-tert-butyl dicarbonate; n-BuLi is n-butyl lithium;tert-BuOH or t-BuOH is tert-butanol; (t-Bu)₃PHBF₄ istri-tert-butylphosphine tetrafluoroborate t-Busphos precatalyst ischloro(2-ditert-butyl-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethyl-phenyl)]palladium(II)dichloromethaneadduct; Bu₄NI is tetrabutyl ammonium iodide; tBuOK is potassiumtert-butoxide; ° C. is degree Celsius; CataCXium A isdi(l-adamantyl)-n-butylphosphine; CDCl₃ is deuterated chloroform; CD₃ODis deuterated methanol; Celite™ is diatomaceous earth; conc. isconcentrated; d is day or days; DAST is diethylaminosulfur trifluoride;DCM is dichloromethane; DEA is N,N-diisopropylethylamine; DEAD isdiethyl azodicarboxylate; DIAD is diisopropyl azodicarboxylate; DIBAL isdiisobutylaluminum hydride; DIEA is diisopropylethylamine; DMA isN,N-dimethylacetamide; DMF is dimethylformamide; DMP is Dess-Martinperiodinane; DMS is dimethyl sulfide; DMSO is dimethylsulfoxide; Et isethyl; EA or EtOAc is ethyl acetate; EtOH is ethanol; Et₂Zn isdiethylzinc; g is grams; Et₃N is triethylamine; Et₃SiH istriethylsilane; iPrOH is isopropyl alcohol; g is gram; G2 Ru Phos ischloro(2-dicyclohexylphosphino-2′,6-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1-biphenyl)]palladium(II);G2 X Phos ischloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II);G418 is Geneticin, an aminoglycoside antibiotic; h is hour; HATU is1-[Bis(dimethylamino)-methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium3-oxide-hexa-fluorophosphate); HPLC is high performance liquidchromatography; KHMDS is potassium hexamethyldisilizide; KOTMS ispotassium trimethylsiloxide; LAH is lithium aluminum hydride; LDA islithium diisopropylamide; LHMDS or LiHMDS is lithiumbis(trimethylsilyl)amide; LiTMP is lithium tetramethylpiperidide; M ismolar; m-CPBA or mCPBA is meta-chloroperoxybenzoic acid; Me is methyl;MeCN is acetonitrile; MeI is methyl iodide; MeOH is methanol; mg ismilligram: MHz is megaHertz; min is minute(s); mmol is millimoles; ml ormL is milliliter; mPa is millipascal; N is normal; nBuLi isn-butyllithium; NBS is N-bromosuccinimide; NCS is N-chlorosuccinimide;NMP is N-methylpyrrolidone; NMR is nuclear magnetic resonance; PCC ispyridinium chlorochromate; Pd—C or Pd/C is palladium(0) on carbon;PdCl₂(dtbpf) is[1,1′-Bis(di-tert-butylphosphino)-ferrocene]di-chloropalladium(II); PEis petroleum ether; Pd(PPh₃)₄ istetrakis(triphenyl-phosphine)palladium(0); Pd(OAc)₂ is palladium (II)acetate; Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium(0);Pd(OH)₂/C is palladium(II)hydroxide on carbon; PPh₃ is triphenylphosphine; prep is preparative; Prep-HPLC is preparative highperformance liquid chromatography; psi is pounds per square inch; PTLCor prep tic is preparative thin layer chromatography; rac is racemic; rtor RT or r.t. is room temperature; RuPhos precatalyst is2-dicyclohexylphosphono-2′,6′-diisopropoxy-biphenyl; sat, or satd. Issaturated; soln. is solution; SelectFluor is1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]-octanebis(tetrafluoroborate); SFC is supercritical fluid chromatography; SPHOSprecatalyst is 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; TBAB istetrabutylammonium bromide; TBAF is tetra-n-butylammonium fluoride; TBAIis tetra-n-butylammonium iodide; TEA is triethylamine; Tf₂O is triflicanhydride or tri-fluoromethanesulfonic anhydride; TFA is trifluoroaceticacid; TFAA is trifluoroacetic anhydride: THF is tetrahydrofuran; TIPS-Clis triisopropyl silylchloride; TLC is thin layer chromatography; TMP istetramethylpiperidine: TMSCl or TMS-Cl is trimethylsilyl chloride;TRIXIEPHOS is 2-Di-t-butylphosphino-1,1′-binaphthyl; PTLC or prep-TLC ispreparative thin layer chromatography; XantPhos is X; and XPHOS, XPhosor Xphos precatalyst is2-dicyclohexylphosphino-2′4′6′-triisopropylbiphenyl.

General Schemes

The compounds of the invention can be prepared using the syntheticschemes described herein as well as any of several alternate methodswhich will be apparent to a chemist skilled in the art.

S8 can be obtained by first reacting the 6-halo-isoquinoline derivativeS1 with the ethyl acrylate using a palladium catalyst to give S3, whichis selectively reduced by hydrogenation with platinum oxide catalysis toyield the ethyl tetrahydroisoquinoline-6-yl-propanoate S5. S5 can becoupled with an aryl halide S6 with a palladium catalyst to give S7. Theacid S8 is obtained after treatment of S7 with LiOH or KOSiMe₃.

S15 can be obtained by protecting the 6-halo-tetrahydroisoquinoline S9at the amino group with a Boc group to give S10. The Boc protectedcompound S10 can further be treated with ethyl acrylate S2 in thepresence of a palladium catalyst to give alkene S11. Alkene S11 can betreated under cyclopropanation conditions with diazomethane in thepresence of palladium acetate to give the cyclopropyl compound S12. TheBoc group is then removed under acidic conditions to give S13 as thehydrochloric acid salt. S13 is then coupled with the aryl halide S6 inthe presence of a palladium catalyst to give S14. S14 can be treatedwith LiOH or KOSiMe₃ to give the acid S15.

S21 can be obtained by first reacting the substituted hydrazine S16 with2-(1-ethoxyethylidene)malononitrile S17 under basic conditions to giveamino-pyrazolyl S18. S18 can be treated with an isoamyl nitrite in thepresence of a copper (1) halide to give the halo-pyrazolyl compound S19.S19 and S5 can be coupled in the presence of a palladium catalyst togive S20, and S20 can be deprotected with LiOH or KOSiMe₃ to give S21.

S30 can be obtained by reacting S10 with carbon monoxide and MeOH in thepresence of a palladium catalyst to give S22. The ester S22 can bereduced in the presence of LiAlH₄ to give the alcohol S23, which may beoxided to the aldehyde in the presence of MnO₂ to give S24. The Bocgroup can be removed using acidic conditions to give the amine S25. Thenamine S25 and S19 can be coupled in the presence of a palladium catalystto give S26. S27 after treatment with NaH can be activated to react withS26 to give the diene S28. The diene S28 can be reduced in the presenceof hydrogen and palladium on carbon to give the alkane S29. S30 can beobtained after treatment of S29 with either LiOH or KOSiMe₃.

S36 can be obtained by first treating s5 with Boc₂O to give the Bocprotected compound S31. S31 can be treated with LiOH to give acid S32.S32 can be treated in peptide coupling conditions in the presence ofNH₄Cl to give amide S33. The amide S33 can be reduced in the presence ofPOCl₃ to give the deprotected cyano compound S34. S34 and S6 can becoupled in the presenced of a palladium catalyst to give S35. S35 can betreated with Bu₃SnN₃ to give the tetrazolyl compound S36.

Intermediate 1 2-(3-Bromo-5-chloro-4-fluorophenoxy)-5-methyl thiazole

Step A. (3-Chloro-4-fluorophenoxy)triisopropylsilane: To a solution of3-chloro-4-fluoro-phenol (20.0 g, 136 mmol) in DMF (100 mL) was added1H-imidazole (9.29 g, 136 mmol) and chlorotriisopropylsilane (26.3 g,136 mmol), and the mixture was stirred at 10° C. for 18 h. The mixturewas diluted with water (500 mL) and extracted with EtOAc (3×150 mL). Theseparated organic layer was dried (MgSO₄), filtered and concentrated invacuo. The resulting residue was purified via silica gel chromatography(PE) to afford the title compound.

Step B. (3-Bromo-5-chloro-4-fluorophenoxy)triisopropylsilane: To a soln.of 2,2,6,6-tetramethylpiperidine (5.60 g, 39.6 mmol) in THF (80 mL) wasadded 2.5 M n-BuLi (16 mL, 40.0 mmol) dropwise at −78° C. under N₂. Thereaction mixture was stirred for 1 h, then the mixture was allowed towarm to 0° C. and stirred for 10 min. The reaction was cooled back to−78° C., and (3-chloro-4-fluorophenoxy)triisopropylsilane (10.0 g, 33.0mmol) in THF (40 mL) was added dropwise at −78° C., and the mixture wasstirred at −78° C. for 2 h. Br₂ (7.91 g, 49.5 mmol) was added, then themixture was stirred at −78° C. for another 2 h. The mixture was quenchedby addition of satd. aq. NH₄Cl (50 mL), diluted with water (100 mL), andextracted with EtOAc (3×150 mL). The organic layer was dried (Na₂SO₄)and concentrated in vacuo. The residue was purified via silica gelchromatography (PE) to afford the title compound.

Step C. 3-Bromo-5-chloro-4-fluorophenol: To a soln. of(3-bromo-5-chloro-4-fluorophenoxy)triisopropylsilane (10.40 g, 27.2mmol) in THF (120 mL) was added TBAF (33 mL, 33.0 mmol), and the mixturewas stirred at 20° C. for 1 h. Then the mixture was diluted with water(150 mL) and extracted with EtOAc (150 mL×3). The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified via silica gel chromatography (PE:EtOAc=50:1) to afford thetitle compound.

Step D. 2-(3-Bromo-5-chloro-4-fluorophenoxy)-5-methylthiazole: A mixtureof 3-bromo-5-chloro-4-fluorophenol (500 mg, 2.218 mmol),2-bromo-5-methylthiazole (434 mg, 2.440 mmol) and Cs₂CO₃ (1.08 g, 3.33mmol) in NMP (6 mL) was stirred under microwave irradiation at 150° C.for 30 min. The mixture was extracted with EtOAc (20 mL×3), and theorganic layer was washed with water (15 mL). The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250*21.2 mm*4 μm) column using water (0.2% TFA) and ACN as eluents(Mobile phase A: water (0.2% TFA). Mobile phase B: ACN, Detectorwavelength: 220 nm) followed by concentration in vacuo to obtain thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd. J=4.89, 2.93 Hz, 1H)7.34 (dd, J=5.48, 2.74 Hz, 1H) 6.91 (s, 1H) 2.38 (s, 3H).

Intermediate 2 2-Bromo-6-cyclobutoxy-3-fluoropyridine

Step A. 2-Cyclobutoxy-5-fluoropyridine: To a suspension of NaH (1.25 g,31.30 mmol) in THF (30 mL) was added cyclobutanol (2.25 g, 31.30 mmol)at rt in one portion, and the mixture was stirred at −25° C. for 10 min,followed by the dropwise addition of 2,5-difluoropyridine (3.00 g, 26.10mmol). The above suspension was stirred at rt for 1 h. The mixture wasdiluted with water (30 mL) and extracted with EtOAc (20 mL). The organiclayer was collected, washed with brine (10 mL), dried over anhyd.Na₂SO₄, filtered, and then concentrated in vacuo to afford the titlecompound. m/z 168.2 [M+H]⁺

Step B. 2-Cyclobutoxy-5-fluoropyridine 1-oxide: To a soln. of2-cyclobutoxy-5-fluoropyridine (1.20 g, 7.18 mmol) in DCM (20 mL) wasadded m-CPBA (2.47 g, 14.36 mmol) at rt in one portion, and the mixturewas stirred at −25° C. for 36 h. The solvent was removed in vacuo, andthe residue was purified by silica gel column chromatography (PE:EtOAcfrom 2:1 to DCM:EtOAc 5:1) to afford the title compound. m/z 184.1[M+H]⁺

Step C. 2-Bromo-6-cyclobutoxy-3-fluoropyridine: To a soln. of2-cyclobutoxy-5-fluoropyridine-1-oxide (400 mg, 2.18 mmol) in toluene (5mL) was added phosphoryl tribromide (689 mg, 2.40 mmol) in one portion,and the mixture was stirred at 100° C. for 1 h. The mixture was added toa satd. aq. NaHCO₃ soln. (10 mL), and then extracted with EtOAc (10 mL).The organic layer was concentrated in vacuo, and the remaining residuewas purified by silica gel PTLC (PE) to afford the title compound.m/z=245.8 [M+H]⁺

Intermediate 3 1-Bromo-5-cyclobutoxy-2,3-difluorobenzene

Step A. 4,5-Difluoro-2-nitrophenol: To a soln. of 3,4-difluorophenol(40.00 g, 307 mmol) in AcOH (100 mL) was added dropwise a soln. offuming nitric acid (18.0 ml, 431 mmol) in AcOH (60 mL) maintaining thetemperature below 50° C. Then the reaction mixture was stirred at 16° C.for 2 h. The reaction mixture was poured into water (200 mL) and thesolid separating out was filtered. The solid was dissolved indichloromethane (200 mL). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to give the title compound which was used directlyin the next step.

Step B. Cyclobutoxy-4,5-difluoro-2-nitrobenzene: To a soln. of4,5-difluoro-2-nitrophenol (45.00 g, 257 mmol) in DMF (200 mL) was addedbromocyclobutane (69.4 g, 514 mmol),mono(4-(tributylammonio)butan-1-ylium) monoiodide (95 g, 257 mmol) andCs₂CO₃ (84 g, 257 mmol). Then the reaction mixture was stirred at 90° C.for 16 h. Water (1.5 L) was added, and the mixture was extracted withEtOAc (300 mL×3). The resulting organic layer was concentrated in vacuo.The crude product was purified by silica gel chromatography (PE toPE/EtOAc=50:1 to 40:1) to give the title compound.

Step C. 2-Cyclobutoxy-4,5-difluoroaniline: To a soln. of1-cyclobutoxy-4,5-difluoro-2-nitrobenzene (5.00 g, 21.82 mmol) in MeOH(60 mL) and water (6 mL) was added NH₄Cl (11.67 g, 218 mmol) and iron(6.09 g, 109 mmol). Then the reaction mixture was stirred at 90° C. for16 h. The reaction mixture was filtered, and water (50 mL) was added tothe filtrate. The filtrate was extracted with EtOAc (30 mL×2), and theorganic layer was concentrated in vacuo to give the crude product whichwas used without further purification.

Step D. 2-Bromo-6-cyclobutoxy-3,4-difluoroaniline: To a soln. of2-cyclobutoxy-4,5-difluoroaniline (2.30 g, 11.55 mmol) in AcOH (50 mL)was added Br₂ (0.68 mL, 13.28 mmol). Then the reaction mixture wasstirred at 14° C. for 16 h. A satd. aq. solution of Na₂S₂O₃ (30 mL) wasadded, and the mixture was extracted with EtOAc (50 mL). The organiclayer was separated and concentrated in vacuo. The crude product waspurified by PTLC (PE/EtOAc=10:1) to give the title compound.

Step E. 1-Bromo-5-cyclobutoxy-2,3-difluorobenzene: To a soln. of2-bromo-6-cyclobutoxy-3,4-difluoroaniline (450 mg, 1.618 mmol) in THF (3mL) was added isopentyl nitrite (380 mg, 3.24 mmol). Then the reactionmixture was stirred at 70° C. for 16 h. The mixture was concentrated invacuo. Water (30 mL) was added, and the mixture was extracted with EtOAc(30 mL×2). The organic layer was concentrated in vacuo, and theresulting crude product purified by silica gel TLC (PE/EtOAc=10:1) togive title compound. ¹H NMR (400 MHz, CDCl₃) δ 6.74 (d, J=2.0 Hz, 1H),6.58-6.61 (m, 1H), 4.53-4.58 (m, 1H), 2.43-2.45 (m, 2H), 2.12-2.17 (m,2H), 1.84-1.87 (m, 2H), 1.65-1.71 (m, 2H).

Intermediate 4 2,3-Difluoro-5-((1R,3R)-3-methoxycyclobutoxy)phenyltrifluoromethanesulfonate

Step A:1-(Benzyloxy)-5-((1r,3r)3-(benzyloxy)cyclobutoxy)-2,3-difluorobenzene:To a solution of 3-(benzyloxy)-4,5-difluorophenol (2.50 g, 10.58 mmol),3-(benzyloxy) cyclobutanol (2.07 g, 11.64 mmol) and PPh₃ (4.16 g, 15.88mmol) in THF (50 mL) was added DIAD (2.9 mL, 14.82 mmol) dropwise withstirring at 0° C. under N₂. After the addition was complete, thereaction mixture was stirred at 70° C. for an additional 18 h under N₂.The solvent was removed in vacuo, and the residue was purified viasilica gel chromatography (PE:EtOAc=50:1 to 20:1) to afford the titlecompound.

Step B. 2,3-Difluoro-5-(3-hydroxycyclobutoxy)phenol: To a solution of1-(benzyloxy)-5-((1r,3r)-3-(benzyloxy)cyclobutoxy)-2,3-difluorobenzene(1.50 g, 3.78 mmol) in MeOH (50 mL) was added 10% Pd—C (600 mg, 2.82mmol). Then the mixture was stirred at rt for 18 h under H₂ (50 Psi).The mixture was filtered, and the filtrate was concentrated in vacuo.The residue was purified via silica gel chromatography (PE:EtOAc=1:1) toafford the title compound.

Step C: 3-(3-(Benzyloxy)-4,5-difluorophenoxy)cyclobutanol: To asuspension of 2,3-difluoro-5-((1r,3r)-3-hydroxycyclobutoxy) phenol (1.00g, 4.63 mmol) and K₂CO₃ (1.279 g, 9.25 mmol) in acetone (30 mL) wasadded (bromomethyl)benzene (0.87 g, 5.09 mmol) dropwise with stirring atrt. Then the mixture was stirred at rt for 48 h. After removing thesolvent in vacuo, the residue was diluted with water (30 mL), extractedwith EtOAc (30 mL×3). The organic layer was dried over anhyd. Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (PE:EtOAc=2:1) to afford title compound.

Step D.1-(Benzyloxy)-2,3-difluoro-5-((1R,3R)-3-methoxycyclobutoxy)benzene: To asoln. of (1R,3R)-3-(3-(benzyloxy)-4,5-difluorophenoxy)cyclobutan-1-olfrom step C (380 mg, 1.241 mmol) in dry DMF (10 mL) was added NaH (60mg, 1.5 mmol) (60% in oil) in portions at 0° C. After 1 h, MeI (528 mg,3.72 mmol) was added dropwise at 0° C. Then the mixture was stirred for18 h with gradual warming to rt. Water (˜10 mL) was added to quench thereaction, and the mixture was diluted with water (100 mL) and extractedwith EtOAc (2×20 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gelchromatography (PE:EtOAc=10:1) to afford the title compound.

Step E. Cis 2,3-Difluoro-5-((1r,3r)-3-methoxycyclobutoxy)phenol: To asoln. of1-(benzyloxy)-2,3-difluoro-5-((1R,3R)-3-methoxycyclobutoxy)benzene (310mg, 0.968 mmol) in MeOH (30 mL) was added 10% Pd—C (50 mg, 0.235 mmol).Then the mixture was stirred at rt for 2 h under H₂ (40 PSI). Themixture was filtered, and the filtrate was concentrated in vacuo to givethe title compound.

Step F. 2,3-Difluoro-5-((1r,3r)-3-methoxycyclobutoxy)phenyltrifluoromethane sulfonate: To a soln. of2,3-difluoro-5-((1r,3r)-3-methoxycyclobutoxy)phenol (200 mg, 0.869 mmol)in DCM (5 mL) was added pyridine (89 mg 1.129 mmol) andtrifluoromethanesulfonic anhydride (319 mg, 1.129 mmol) dropwise withstirring at 0° C. Then the mixture was stirred at rt for 3 h. Water (10mL) was added, and the mixture was extracted with DCM (20 mL×2). Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (PE:EtOAc=20:1) toafford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 6.65 (ddd, J=11.05,5.77, 2.74 Hz, 1H) 6.52-6.56 (m, 1H) 4.73-4.79 (m, 1H) 4.10-4.16 (m, 1H)3.28 (s, 3H) 2.37-2.50 (m, 4H).

Intermediate 5 1-Bromo-3-chloro-2-fluoro-5-(trifluoromethoxy)benzene

Step A. 1-Bromo-2-fluoro-4-nitro-5-(trifluoromethoxy)benzene: To a soln.of 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (10.0 g, 38.6 mmol) inACN (150 mL) was added nitronium tetrafluoroborate (5.38 g, 40.5 mmol)at 0° C., and the mixture was stirred at 0-18° C. for 16 h. The reactionmixture was extracted with EtOAc (3×200 mL), and washed with water(2×150 mL) and brine (2×150 mL). The organic layer was dried over anhyd.Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. Theresulting residue was purified by silica gel chromatography(PE:EtOAc=20:1 to 5:1) to give the title compound.

Step B. 4-Bromo-5-fluoro-2-(trifluoromethoxy)aniline: To a stirred soln.of 1-bromo-2-fluoro-4-nitro-5-(trifluoromethoxy)benzene (4.0 g, 13.16mmol) in MeOH (20 mL) and water (2 mL) was added NH₄Cl (7.04 g, 132mmol) and iron (2.204 g, 39.5 mmol). The mixture was stirred at 50° C.for 18 h. The mixture was washed with water (2×30 mL) and extracted withEtOAc (2×50 mL). The extract was dried over by Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1) to give the title compound.

Step C. 4-Bromo-2-chloro-3-fluoro-6-(trifluoromethoxy)aniline: To astirred soln. of 4-bromo-5-fluoro-2-(trifluoromethoxy)aniline (750 mg,2.74 mmol) in ACN (30 mL) was added 1-chloropyrrolidine-2,5-dione (365mg, 2.74 mmol) and the mixture was stirred at 50° C. for overnight (18h). The mixture was washed with water (2×10 mL) and extracted with EtOAc(2×30 mL). The organic layer was dried over anhyd. Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE:EtOAc=50:1 to 30:1) to give the title compound.

Step D. 1-Bromo-3-chloro-2-fluoro-5-(trifluoromethoxy)benzene: To astirred soln. of 4-bromo-2-chloro-3-fluoro-6-(trifluoromethoxy)aniline(300 mg, 0.973 mmol) in THF (5 mL) was added isopentyl nitrite (228 mg,1.945 mmol), and the mixture was stirred at 50° C. for 4 h. The mixturewas washed with water (2×10 mL) and extracted with EtOAc (2×30 mL). Thecombined organic layer was dried over anhyd. Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by TLC (PE:EtOAc=10:1)to give the title compound.

Intermediate 6 4-bromo-3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole

Step A. 5-(4-chlorophenyl)-1,3,4-oxathiazol-2-one. To a solution of4-chlorobenzamide (3.0 g, 17.35 mmol) in toluene (10 ml) was addedcarbonochloridic hypochlorous thioanhydride (4.55 g, 34.7 mmol) at ˜20°C. Then the mixture was stirred overnight (˜18 h) at 100° C. Theresulting mixture was concentrated in vacuo. The resulting residue waspurified by column chromatography on silica gel (EtOAc/PE=1:20) to givethe title compound.

Step B—ethyl3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole-4-carboxylate: Into a100 mL sealed tube was placed 5-(4-chlorophenyl)-1,3,4-oxathiazol-2-one(2.2 g, 9.78 mmol), ethyl 4,4,4-trifluorobut-2-ynoate (2.437 g, 14.67mmol) and 1,3-dichlorobenzene (20 ml). The resulting solution wasstirred for 18 h at 130° C. The mixture was stirred at 150° C. for 5 h.The resulting mixture was concentrated in vacuo. The resulting residuewas purified by silica gel column chromatography (PE) to give the titlecompound.

Step C. 3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole-4-carboxylicacid: To a solution of ethyl3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole-4-carboxylate (2.6 g,6.58 mmol) in THF (10 mL) and water (5 mL) was added LiOH hydrate (0.829g, 19.75 mmol). Then the mixture was stirred at rt for 18 h. Afteracidification with 1N HCl to pH=2, the solvent was removed in vacuo. Theresidue was purified by silica gel column chromatography (EtOAc/PE=10:1to 1:1) to give the title compound.

Step D. tert-butyl(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl) carbamates: To amixture of3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole-4-carboxylic acid (600mg, 1.755 mmol) and Et₃N (195 mg, 1.931 mmol) in t-BuOH (20 ml) wasadded diphenylphosphoryl azide (531 mg, 1.931 mmol) at rt. Then themixture was refluxed for 3 h. The reaction mixture was concentrated invacuo, and the residue was partitioned between EtOAc (30 mL) and H₂O (30mL). The organic layer was washed with brine (30 mL), dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (EtOAc/PE 1:20) to give the title compound.

Step E. 3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-amine: To asolution of tert-butyl(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)carbamate (590mg, 1.246 mmol) in EtOAc (10 ml) was added HCl/EtOAc (3 ml, 4 M indioxane) at rt. Then the mixture was stirred rt (under an N₂ atmosphere)for 18 h. The mixture was concentrated in vacuo to give crude product.To the crude product was added EtOAc (20 mL) and water (20 mL) basifiedwith saturated Na₂CO₃ to pH=7-8. Then the mixture extracted with EtOAc(2×10 mL). The organic layer was washed with brine (20 mL), dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (EtOAc/PE=20:1) to give thetitle compound.

Step F. 4-bromo-3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole: To asolution of 3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-amine (50mg, 0.161 mmol) in MeCN (2 mL) was added CuBr₂ (72 mg, 0.322 mmol) andtert-butyl nitrite (37 mg, 0.359 mmol) at 0° C., and the mixture wasstirred at 0° C. for 30 min. The mixture was concentrated in vacuo andwashed with water (10 mL), and extracted with EtOAc (2×0 mL). Thecombined organic layer was washed with brine (2×0 mL) and concentratedin vacuo to give the crude product, which was purified by silica gelchromotography (PE:EtOAc=50:1) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 7.78 (d, J=8.41 Hz, 2H) 7.49 (d, J=8.41 Hz, 2H).

Intermediate 7 Ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A. (E)-ethyl 3-(isoquinolin-6-yl)acrylate: To a solution of6-bromoisoquinoline (10.0 g, 48.06 mmol) in dry 1,4-dioxane (100 ml) wasadded tri-tert-butylphosphonium tetrafluoroborate (1.4 g, 4.8 mmol),ethyl acrylate (7.22 g, 72.10 mmol) andN-cyclohexyl-N-methylcyclo-hexanamine (28.17 g, 144.19 mmol). Then themixture was degassed for 5 min with N₂, and Pd₂(dba)₃ (3.5 g, 4.8 mmol)was added. The mixture was stirred at 100° C. for 18 h under a N₂atmosphere. The mixture was extracted with EtOAc (2×200 mL), washed withbrine (500 mL), dried (Na₂SO₄), and then purified by chromatography(PE:EtOAc=20:1 to 10:1) to give the title compound.

Step B. ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate: To asolution of (E)-ethyl 3-(isoquinolin-6-yl)acrylate (9.0 g, 39.60 mmol)in EtOH (150 ml) was added platinum (IV) oxide (0.899 g, 3.96 mmol). Thereaction mixture was stirred under hydrogen (50 PSI) at 60° C. for 5 h.The reaction mixture was cooled to rt, the mixture was filtered, and thefiltrate was concentrated in vacuo to give the title compound. m/z 234.3[M+H]⁺.

Intermediate 8 2-Bromo-4-(cyclobutyldifluoromethyl)-1-fluorobenzene

Step A: 3-Bromo-4-fluoro-N-methoxy-N-methylbenzamide: To a soln. of DIEA(4.78 ml, 27.4 mmol), 3-bromo-4-fluorobenzoic acid (2.0 g, 9.13 mmol)and N,O-dimethylhydroxylamine hydrochloride (0.891 g, 9.13 mmol) in DMF(25 ml) was added HATU (3.47 g, 9.13 mmol) at 0° C., and the mixture wasstirred 18 h (0° C.→rt). The mixture was poured into water (100 mL),extracted with EtOAc (3×200 mL), washed with water (5×50 mL) and brine(2×50 mL). The organic soln. was dried over Na₂SO₄, the salt wasfiltered off, and the filtrate was concentrated in vacuo. The residuewas purified by silica gel chromatography (PE:EtOAc=20:1 to 5:1) to givethe title compound. m/z 264.0 [M+H]⁺.

Step B. (3-Bromo-4-fluorophenyl)(cyclobutyl)methanone: To a suspensionof magnesium (0.538 g, 22.13 mmol) in THF (20 ml) was added I₂ (0.028 g,0.111 mmol) at 40° C., the mixture was stirred at 40° C. for 10 min, andthen bromocyclobutane (2.99 g, 22.13 mmol) was added dropwise withstirring at 10° C. (N₂ atmosphere). After the addition was complete, thereaction mixture was stirred at 40° C. for additional 2 h. The abovesoln. was added dropwise to a soln. of3-bromo-4-fluoro-N-methoxy-N-methylbenzamide (2.9 g, 11.07 mmol) in THF(30 mL) at 0° C. (under N₂ atmosphere). The mixture was stirred for 16 h(0° C.-rt). The reaction mixture was poured into ice water (20 mL), andthe mixture was extracted with EtOAc (2×30 mL). The combined organiclayer was washed with brine (2×20 mL) and then dried over anhyd. Na₂SO₄.The organic layer was filtered and concentrated in vacuo to give crudeproduct. The crude product was purified by silica gel columnchromatography (PE/DCM=100:1 to 5:1) to give compound the titlecompound.

Step C. 2-bromo-4-(cyclobutyldifluoromethyl)-1-fluorobenzene: To a soln.of (3-bromo-4-fluorophenyl)(cyclobutyl)methanone (300 mg, 1.167 mmol) inDAST (3.0 ml, 16.27 mmol) was added dropwise MeOH (7.58 μl, 0.187 mmol)with stirring at 0° C. (under N₂ atmosphere). After the addition wascomplete, the reaction mixture was stirred at 80° C. for additional 3days. The reaction mixture was cooled to rt, and poured into sat. Na₂CO₃(10 mL). Then the mixture was extracted with PE (˜20 mL×2). The combinedorganic layers were washed with brine (˜10 mL×2), dried over Na₂SO₄,filtered, and concentrated in vacuo to give crude product. The crudeproduct was purified by PTLC (PE) to give the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.66 (d, J=5.5 Hz, 1H), 7.37 (br. s., 1H), 7.15 (t,J=8.4 Hz, 1H), 3.03-2.85 (m, 1H), 2.27-2.11 (m, 2H), 2.05-1.77 (m, 4H).

Intermediate 9 2,3-Difluoro-5-(3-methylcyclobutoxy)phenyltrifluormethanesulfonate

Step A.1-(benzyloxy)-5-(3-(bromomethyl)cyclobutoxy)-2,3-difluoro-benzene: To astirred soln. of(3-(3-(benzyloxy)-4,5-difluorophenoxy)cyclobutyl)methanol (800 mg, 2.498mmol) and CBr₄ (1.24 g, 3.75 mmol) in DMF (8 mL) was added PPh₃ (982 mg,3.75 mmol) portionwise at 0° C. Then the reaction mixture was stirred atrt for 2 h. The mixture was diluted with water (50 mL) and extractedwith EtOAc (2×30 mL). The organic layer was concentrated in vacuo, andthe crude product was purified by silica gel chromatography(PE/EtOAc=40:1) to give the title compound.

Step B. 1-(benzyloxy)-2,3-difluoro-5-(3-methylcyclobutoxy)benzene: To astirred soln. of1-(benzyloxy)-5-(3-(bromomethyl)cyclobutoxy)-2,3-difluorobenzene (580mg, 1.51 mmol) in DMF (8 mL) was added NaBH₄ (115 mg, 3.03 mmol). Thenthe reaction mixture was placed under N₂ and stirred at rt for 18 h. Thereaction was quenched with satd. aq. of NH₄Cl (20 mL), extracted withEtOAc (20 mL×2), washed with water (100 mL), and the organic layer wasconcentrated in vacuo. The crude product was purified by silica gelchromatography (PE/EtOAc=5:1) to give the title compound.

Step C. 2,3-difluoro-5-(3-methylcyclobutoxy)phenol: A mixture of1-(benzyloxy)-2,3-difluoro-5-(3-methylcyclobutoxy)benzene (390 mg, 1.28mmol) and 10% Pd—C (100 mg, 0.094 mmol) in MeOH (50 mL) was stirredunder hydrogen (40 PSI) at rt for 2 h. The mixture was filtered andconcentrated in vacuo to give the crude title compound.

Step D. 2,3-difluoro-5-(3-methylcyclobutoxy)phenyltrifluormethanesulfonate: To a stirred soln. of2,3-difluoro-5-(3-methylcyclobutoxy)phenol (200 mg, 0.934 mmol) in DCM(5 mL) was added pyridine (96 mg, 1.214 mmol) andtrifluoromethanesulfonic anhydride (342 mg, 1.214 mmol) dropwise at 0°C. Then the reaction mixture was warmed to rt for 5 h. The solvent wasevaporated in vacuo, and the resulting mixture was diluted with water(20 mL) and extracted with EtOAc (20 mL×2). The organic layer wasconcentrated in vacuo, and the crude product was purified by silica gelchromatography (PE/EtOAc=10:1) to give the title compound.

Intermediate 10 2-(5-Bromo-4-fluoro-2-methoxyphenoxy)-5-methylthiazole

Step A. 5-Bromo-4-fluoro-2-methoxyphenol: To a soln. of4-fluoro-2-methoxyphenol (2.0 g, 14.07 mmol) in MeCN (40 mL) was addedNBS (2.63 g, 14.78 mmol) at 0° C., and the mixture was stirred at rt for18 h. After removing the solvent in vacuo, the residue was extractedwith EtOAc (60 mL) and water (60 mL). The organic layer was separated,dried and concentrated in vacuo. The residue was purified via silica gelchromatography (PE:EtOAc=100:1) to afford the title compound.

Step B. 2-(5-Bromo-4-fluoro-2-methoxyphenoxy)-5-methylthiazole: Amixture of 2-bromo-5-methylthiazole (300 mg, 1.68 mmol),5-bromo-4-fluoro-2-methoxyphenol (410 mg, 1.85 mmol) and K₂CO₃ (466 mg,3.37 mmol) in DMF (10 mL) was stirred at 120° C. for 18 h. The mixturewas diluted with water (200 mL) and extracted with EtOAc 3×20 mL). Theorganic layer was dried and concentrated in vacuo. The residue waspurified via prep-HPLC to afford the title compound. m/z 319 [M+H]⁺.

Intermediate 11 5-Bromo-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile

Step A. 5-Amino-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile: To asoln. of p-tolylhydrazine hydrochloride (50 g, 315 mmol) in EtOH (400ml) was added TEA (132 ml, 946 mmol), and the reaction mixture wasstirred at rt for 40 min. Then 2-(1-ethoxyethylidene)-malononitrile(38.6 g, 284 mmol) was added slowly at 0° C., and the reaction mixturewas stirred at 25° C. for 12 h. The reaction mixture was partitionedbetween EtOAc (200 mL) and water (200 mL), and the separated organiclayer was washed with brine (200 mL). The organic layer was dried(Na₂SO₄) and concentrated in vacuo. and the resulting residue waspurified by silica gel chromatography (PE/EtOAc 5:1 to 1:1) to give thetitle compound. m/z 213.2 [M+H]⁺.

Step B. 5-Bromo-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile: To asoln. of 5-amino-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile (10 g,47.1 mmol) and CuBr (10.14 g, 70.7 mmol) in MeCN (100 mL) was addedisopentyl nitrite (11.04 g, 94 mmol) dropwise. The reaction mixture wasstirred at 25° C. under a N₂ atmosphere for 2 h. The reaction mixturewas partitioned between EtOAc (60 mL) and water (60 mL), and theseparated organic layer was washed with brine (60 mL). The organic layerwas concentrated in vacuo, and the residue was purified by silica gelchromatography (PE/EtOAc 15:1-10:1) to give the title compound. m/z276.1 [M+H]⁺.

Intermediate 12 2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methylpyridine

Step A. 2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methyl-3-nitropyridine:A mixture of 2-chloro-5-methyl-3-nitropyridine (2 g, 10.5 mmol),5-bromo-4-fluoro-2-methoxyphenol (2.56 g, 10.5 mmol) and K₂CO₃(4.8 g,34.8 mmol) in DMF (20 mL) was stirred at rt overnight. The mixture waspoured into cold water (100 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, and the organic layerwas concentrated in vacuo. The resulting residue was stirred with PE (10mL) for 30 min., and the solid that separated was filtered off to givethe title compound.

Step B. 2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methylpyridin-3-amine:To a mixture of2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methyl-3-nitropyridine (2.7 g,7.56 mmol) and iron powder (1.7 g, 30.4 mmol) in EtOH (25 mL) was addeda soln. of NH₄Cl (1.0 g, 18.9 mmol) in water (3 mL) dropwise at 55-60°C. After addition, the mixture was heated to reflux for 3 h. Thereaction mixture was filtered through Celite™, and the filtrate wasconcentrated in vacuo. The residue was dissolved in EtOAc (20 mL), andthe organic layer was washed with water (10 mL) and brine (10 mL). Theorganic layer was concentrated in vacuo to give the title compound.

Step C: 2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methylpyridine: To thesoln. of 2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methylpyridin-3-amine(2.0 g, 6.1 mmol) in THF (20 mL) was added dropwise a soln. of isopentylnitrite (1.4 g, 12.2 mmol) in THF (3 mL) at rt under N₂. Then thereaction mixture was heated to reflux for 3 h. The reaction mixture wasconcentrated in vacuo. and the resulting residue was purified by silicagel chromatography (PE:EA=20:1) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 7.93 (s, 1H) 7.48-7.56 (m, 1H) 7.30 (d, J=7.04 Hz, 1H)6.77-6.92 (m, 2H) 3.71-3.81 (m, 3H) 2.28 (s, 3H).

Intermediate 13 (2-(Cyclobutylthio)-5-fluoropyridin-4-yl)boronic acid

Step A. 5-Fluoropyridine-2-thiol: Prepared from 5-fluoropyridin-2-olaccording to the procedure described in US 2012/0309796.

Step B. 2-(Cyclobutylthio)-5-fluoropyridine: A reaction vial was chargedwith Cs₂CO₃ (652 mg, 2.00 mmol) and 5-fluoro-2-thiopyridone (129 mg, 1mmol). The vial was sealed and flushed with N₂. Dry DMF (5 mL) andbromocyclobutane (113 μl, 1.200 mmol) were added via syringe. The tubewas heated (50° C.) for 2 h. The mixture was diluted with EtOAc (20 mL)and washed with water (2×10 mL). The organic layer was washed with brine(5 mL), dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (0 to 30%EtOAc/hexanes) to give the title compound. m/z 184.50 [M+H]⁺

Step C. (2-(Cyclobutylthio)-5-fluoropyridin-4-yl)boronic acid: Athree-necked round-bottom flask was charged with a soln. ofdiisopropylamine (0.097 ml, 0.682 mmol) in dry THF (2 ml). The solutionwas cooled to −20° C. and 2.5 M n-BuLi (0.262 ml, 0.655 mmol) was added.The soln was stirred for 10 min and then warmed to 0° C. for 10 min. Thesoln. was cooled to −78° C. and a soln. of2-(cyclobutylthio)-5-fluoropyridine (100 mg, 0.546 mmol) from step B indry THF (3 ml) was added dropwise. The mixture was stirred for 1 h,followed by the addition of trimethyl borate (0.305 ml, 2.73 mmol). Themixture was gradually warmed to rt and stirred for 4 h. The reaction wasquenched by addition of aq. 1 M HCl (10 mL), and the mixture was stirredfor 10 min. The product was extracted with EtOAc (2×15 mL). The combinedorganic layers were washed with brine (5 mL), dried over MgSO₄, filteredand concentrated in vacuo. The crude product was used for next stepwithout further purification. m/z 228.17 [M+H]⁺

Intermediate 14 1-Bromo-3-chloro-5-cyclobutoxy-2-fluorobenzene

Step A. 2-chloro-4-cyclobutoxy-1-fluorobenzene: To a soln. of3-chloro-4-fluorophenol (5 g, 34.12 mmol) in DMF (50 mL) was addedbromocyclobutane (9.21 g, 68.24 mmol), Bu₄NI (12.60 g, 34.12 mmol) andCs₂CO₃ (11.12 g, 34.12 mmol). Then the mixture was stirred at 90° C. for18 h. The mixture was extracted with EtOAc (3×100 mL) and water (600mL), and the organic layer was separated, dried and concentrated invacuo. The residue was purified by silica gel chromatography (PE) toafford the title compound.

Step B. 1-bromo-3-chloro-5-cyclobutoxy-2-fluorobenzene: To a soln. of2,2,6,6-tetramethyl-piperidine (0.845 g, 5.98 mmol) in THF (20 mL) wasadded dropwise n-BuLi (2.5 M, 2.4 mL, 6.00 mmol) at −78° C. under N₂.After 20 min, the mixture was allowed to warm to 0° C. and stirred for10 min. Then 2-Chloro-4-cyclobutoxy-1-fluorobenzene (1.0 g, 4.98 mmol)in THF (5 mL) was added dropwise to the mixture at −78° C. The mixturewas stirred at −78° C. for 40 min. Then bromine (1.195 g, 7.48 mmol) wasadded, and the mixture was stirred at −78° C. for 40 min. The mixturewas quenched with satd. aq. NH₄Cl (10 mL), and extracted with EtOAc(3×30 mL) and water (20 mL). The organic layer was separated, dried andconcentrated in vacuo. The residue was purified by silica gelchromatography (PE) to afford the title compound. ¹HNMR (400 MHz, CDCl₃,ppm): δ 1.63-1.72 (m, 1H) 1.85 (q, J=10.30 Hz, 1H) 2.07-2.17 (m, 2H)2.37-2.47 (m, 2H) 4.53 (quin, J=6.95 Hz, 1H) 6.77 (dd, J=5.28, 2.93 Hz,1H) 6.87 (dd, J=4.89, 2.93 Hz, 1H).

Intermediate 15 4-Fluoro-1-(4-fluorophenyl)-5-iodo-3-methyl-1H-pyrazole

Step A. 1-(4-Fluorophenyl)-3-methyl-1H-pyrazol-5-amine: To a soln. of(4-fluorophenyl)-hydrazine hydrochloride (30.0 g, 185 mmol) in EtOH (100mL) was added Et₃N (56.0 g, 554 mmol) and2-(ethoxymethylene)malononitrile (23.66 g, 194 mmol). After the additionwas complete, the reaction mixture was stirred 70° C. for 15 h. Thereaction mixture was cooled to rt and concentrated in vacuo. Then themixture was extracted with EtOAc (2×100 mL). The combined organic layerwas washed with brine, and then dried over Na₂SO₄, filtered andconcentrated in vacuo to give crude product. The crude product waspurified by silica gel column chromatography (PE/EtOAc 10:1 to 5:1) togive the title compound.

Step B. 4-fluoro-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-amine: To asoln. of 1-(4-fluoro-phenyl)-3-methyl-1H-pyrazol-5-amine (10.0 g, 52.3mmol) in THF (50 mL) was added Selectfluor® (18.53 g, 52.3 mmol). Afterthe addition was complete, the mixture was stirred at rt for 15 h. Thereaction was concentrated in vacuo, and the mixture was extracted withEtOAc (2×50 mL). The organic layer was washed with brine, then driedover Na₂SO₄, filtered and concentrated in vacuo to give the crudeproduct. The crude product was purified by silica gel columnchromatography (PE/EtOAc 30:1 to 10:1) to give the title compound.

Step C. 4-fluoro-1-(4-fluorophenyl)-5-iodo-3-methyl-1H-pyrazole: To asoln. of 4-fluoro-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-amine (2.0 g,9.56 mmol) in MeCN (30 mL) was added isobutyl nitrite (2.465 g, 23.90mmol) and CuI (3.64 g, 19.12 mmol). After the addition was complete, themixture was stirred at 60° C. for 1 h. The reaction mixture was cooledto rt, filtered, and concentrated in vacuo. Then the mixture wasextracted with EtOAc (50 mL×2). The combined organic layer was washedwith brine, and then dried over Na₂SO₄, filtered and concentrated invacuo to give the crude product. The crude product was purified bysilica gel column chromatography (PE/EtOAc 30:1 to 10:1) to give thetitle compound. m/z 321.0 [M+H]⁺

Intermediate 16 2-Chloro-6-(cyclobutylthio)pyridine

Step A: 6-chloropyridine-2-thiol: To a mixture of 6-chloropyridin-2-ol(2.00 g, 15.44 mmol) and Lawesson's reagent (6.56 g, 16.21 mmol) wasadded THF (50 mL), and the soln. was stirred at about 80° C. overnightunder a N₂ atmosphere. The soln. was concentrated in vacuo to give thecrude product which was purified by silica gel chromatography(PE:EtOAc=6:1) to afford the title compound.

Step B: 2-chloro-6-(cyclobutylthio)pyridine: To a mixture of6-chloropyridine-2-thiol (270 mg, 1.85 mmol) in DMF (3 mL) was addedbromocyclobutane (250 mg, 1.85 mmol) and Cs₂CO₃ (725 mg, 2.23 mmol).Then the soln. was stirred at 100° C. about 2 h. The soln. was treatedwith H₂O (20 mL) and extracted with EtOAc (10 mL×3). The combinedorganic layer was washed with brine (10 mL), and then dried over anhyd.Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by silica gel chromatography (PE:EtOAc=20:1) to afford thetitle compound. ¹H NMR (400 MHz, CDCl₃) ppm 7.40 (t, J=7.83 Hz, 1H),6.96 (dd, J=7.83, 2.74 Hz, 1H), 4.30 (quin, J=7.92 Hz, 1H), 2.49-2.62(m, 2H), 2.00-2.19 (m, 4H).

Intermediate 17 2-Chloro-6-cyclobutoxypyrazine

To a suspension of NaH (322 mg, 8.05 mmol) in THF (10 ml) was addedcyclobutanol (581 mg, 8.05 mmol), and the mixture was stirred at rt for15 min. To this soln. was added 2,6-dichloropyrazine (1 g, 6.71 mmol),and the mixture was stirred at 50° C. for 18 h. The soln. was dilutedwith H₂O (20 mL), and the mixture was extracted with EtOAc (3×20 mL).The combined organic layer was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to afford crude product. Theresidue was purified by silica gel chromatography (PE) to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) ppm 8.09 (d, J=16.82 Hz, 2H), 5.17 (q,J=7.34 Hz, 1H), 2.43-2.52 (m, 2H), 2.10-2.20 (m, 2H), 1.86 (q, J=10.30Hz, 1H), 1.62-1.75 (m, 1H).

Intermediate 18 4-Chloro-5-iodo-3-methyl-1-(p-tolyl)-1H-pyrazole

Step A: 4-Chloro-3-methyl-1-(p-tolyl)-1H-pyrazol-5-amine: To a soln. of3-methyl-1-(p-tolyl)-1H-pyrazol-5-amine (3.0 g, 16.02 mmol, synthesizedusing similar conditions as described for the fluoro intermediate 15) inMeCN (50 mL) was added NCS (2.35 g, 17.62 mmol), and the mixture wasstirred at rt (˜25° C.) for 18 h. Then the solvent evaporated in vacuo.and the resulting residue was desolved in EtOAc (100 mL), washed withH₂O (60 mL×3) and brine (60 mL), The organic layer was concentrated invacuo and purified by silica gel chromatography (PE:EtOAc=10:1) to givethe title compound. m/z 221.6 [M+H]⁺.

Step B: 4-Chloro-5-iodo-3-methyl-1-(p-tolyl)-1H-pyrazole: To a soln. of4-chloro-3-methyl-1-(p-tolyl)-1H-pyrazol-5-amine (2.5 g, 11.28 mmol) inMeCN (50 mL) was added CuI (6.44 g, 33.84 mmol) and isopentyl nitrite(3.30 g, 28.19 mmol) at 0° C. Then the reaction mixture was stirredunder reflux for 3 h. The solvent was evaporated in vacuo. and theresidue was dissolved in EtOAc (100 mL). The organic layer was washedwith H₂O (60 mL×3) and brine (60 mL). Then the organic layer wasconcentrated in vacuo. and the residue was purified by silica gelchromatography (PE:EtOAc=50:1) to give the title compound. m/z 332.9[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.34 (s, 3H), 2.40 (s,3H),7.23-7.28 (m, 3H), 7.29-7.37 (m, 2H).

Intermediate 19 2-Bromo-4-cyclobutoxy-6-fluorobenzonitrile

Step A. 1-Bromo-3-cyclobutoxy-5-fluorobenzene: To a soln. of3-bromo-5-fluorophenol (3.0 g, 15.71 mmol) in DMF (15 mL) was addedbromocyclobutane (4.24 g, 31.41 mmol), Bu₄NI (5.80 g, 15.71 mmol) andCs₂CO₃ (5.12 g, 15.71 mmol). Then the mixture was stirred at 90° C.overnight. The mixture was extracted with EtOAc (90 mL) and water (300mL). The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified via silica gel chromatography (PE) to afford thetitle compound.

Step B. 2-Bromo-4-cyclobutoxy-6-fluorobenzaldehyde: To a soln. of2,2,6,6-tetramethyl-piperidine (692 mg, 4.90 mmol) in THF (10 mL) wasadded n-BuLi (2.5 M, 1.96 mL, 4.90 mmol) at −78° C. under N₂. After 30min. 1-bromo-3-cyclobutoxy-5-fluorobenzene (1 g, 4.08 mmol) in THF (5mL) was added dropwise at −78° C. under N₂. Then the mixture was stirredat −78° C. for 40 min. DMF (447 mg, 6.12 mmol) was added, and themixture was stirred at −78° C. for 1 h. The reaction was quenched withsaturated NH₄Cl soln., acidified to pH 1-2 with 6 N HCl, thenpartitioned with EtOAc (30 mL) and water (20 mL). The organic layer wasdried (Na₂SO₄) and concentrated in vacuo. The residue was purified viasilica gel (PE:EtOAC=100:1) to afford the title compound.

Step C. (E)-2-Bromo-4-cyclobutoxy-6-fluorobenzaldehyde oxime: To a soln.of 2-bromo-4-cyclobutoxy-6-fluorobenzaldehyde (700 mg, 2.56 mmol) inEtOH (10 mL), was added NH₂OH (aq., 50% w/w, 340 mg, 5.13 mmol). Thenthe mixture was stirred at 100° C. for 2 h. After cooling to rt, themixture was poured onto ice and stirred for 30 min. The resultingsuspension was filtered, and the cake was dried to afford the titlecompound. m/z 288 [M+H]⁺.

Step D: 2-Bromo-4-cyclobutoxy-6-fluorobenzonitrile: To a soln. of(E)-2-bromo-4-cyclobutoxy-6-fluorobenzaldehyde oxime (650 mg, 2.26 mmol)in DMF (5 mL) was added POCl₃ (865 mg, 5.64 mmol) dropwise at 0° C. Thenthe mixture was allowed to warm to rt and stirred for 4 h. The mixturewas poured into water, and the mixture was stirred for 1 h. The mixturewas extracted with EtOAc (30 mL) and water (100 mL). The organic layerwas dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedvia silica gel chromatography (PE:EtOAc=50:1) to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃, ppm): δ 1.70-1.78 (m, 1H) 1.89-1.97(m, 1H) 2.15-2.25 (m, 2H) 2.48 (d, J=7.43 Hz, 2H) 4.61-4.68 (m, 1H) 6.57(d, J=10.56 Hz, 1H) 6.92 (br. s., 1H).

Intermediate 20 1-Bromo-2-chloro-5-cyclobutoxy-4-methoxybenzene

Step A. 4-chloro-1-cyclobutoxy-2-methoxybenzene: To a soln. of4-chloro-2-methoxyphenol (5.0 g, 31.5 mmol) in 50 mL of DMF was slowlyadded bromocyclobutane (8.50 g, 63.0 mmol), Cs₂CO₃ (20.52 g, 63.0 mmol)and Bu₄NI (11.64 g, 31.6 mmol). The mixture was stirred at 90° C.overnight. The mixture was diluted with water (400 mL), extracted withEtOAc (100 mL), and concentrated in vacuo. The resulting residue waspurified by silica gel flash column chromatography (Petroleumether/ethyl acetate=100:1) to give the title compound.

Step B: 1-bromo-2-chloro-5-cyclobutoxy-4-methoxybenzene: To a soln. of4-chloro-1-cyclobutoxy-2-methoxybenzene (2 g, 9.49 mmol) in MeCN (20 mL)was slowly added NBS (1.832 g, 10.44 mmol). The mixture was stirred atrt for overnight. The mixture was extracted with EtOAc (100 mL), and theorganic layer was washed with H₂O (50 mL×3), and concentrated in vacuo.The residue was purified by silica gel flash column chromatography(Petroleum ether/ethyl acetate=100:1) to afford the title compound. ¹HNMR (400 MHz, CDCl₃) ppm 6.91 (d, J=8.78 Hz, 2H) 4.61 (quin, 1=7.15 Hz,1H) 3.84 (s, 3H) 2.42-2.52 (m, 2H) 2.17-2.29 (m 2H) 1.87 (q, J=10.29 Hz,1H) 1.64-1.75 (m, 1H).

Intermediate 21 2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)pyridine

Step A. 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde: To astirred soln. of 2,2,6,6-tetramethylpiperidine (18.06 g, 0.13 mol) inTHF (250 mL) in a three necked round bottom flask was added n-BuLi (2.5M, 51.1 mL, 0.13 mmol) dropwise at −78° C. over 0.5 h. Then the mixturewas stirred at 0° C. for 0.5 h. A solution of(3-bromo-4-fluorophenoxy)-triisopropylsilane (37.0 g, 0.11 mmol) in THF(300 mL) was added to the above mixture dropwise at −78° C. over 0.5 h.The mixture was stirred for 1 h, and then DMF (15.57 g, 213 mmol) wasadded. The mixture was diluted with water (300 mL) and extracted withEtOAc (2×100 mL). The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel column chromatography (PE:EtOAcfrom 20:1 to 1:1) to afford 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde and 3-bromo-2-fluoro-5-hydroxybenzaldehyde.

Step B-3-bromo-5-(difluoromethyl)-4-fluorophenol: To a stirred solutionof 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde (22.00 g,58.60 mmol) in DCM (200 mL) was added DAST (11.62 ml, 88.00 mmol)dropwise at 0° C., and the resulting mixture was allowed to warm to rtfor 2 h with stirring. The mixture was poured into a diluted NaHCO₃solution to adjust the pH of the mixture to about pH 5, then dilutedwith water (100 mL), extracted with DCM (100 mL). The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄, and filtered.The organic layer was concentrated in vacuo. The resulting residue waspurified by silica gel column chromatography (PE:EtOAc from 20:1 to 5:1)to give the title compound.

Step C-3-bromo-5-(difluoromethyl)-4-fluorophenol: A mixture of(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)triisopropylsilane (10.0 g,25.2 mmol) and TBAF (7.90 g, 30.2 mmol) in THF (50 ml) was stirred at15° C. for 2 h. The mixture was diluted with water (50 mL) and extractedwith EtOAc (50 mL). The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, and filtered, and the concentrated invacuo. The crude product was purified by silica gel columnchromatography (PE:EtOAc from 10:1 to 3:1) to afford the title compound.

Step D-2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)pyridine: A mixtureof 2-fluoro-pyridine (200 mg, 2.06 mmol) and3-bromo-5-(difluoromethyl)-4-fluorophenol (596 mg, 2.47 mmol), Cs₂CO₃(1.34 g, 4.12 mmol) in NMP (5 mL) was heated at 140° C. under microwaveirradiation for 1 h. The mixture was diluted with water (20 mL), andextracted with EtOAc (20 mL). The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The crude product was further purified by reverse phase HPLC on aGILSON 281 instrument fitted with a Phenomenex Synergi C18 (250×21.2mm×4 μm) using water (0.2% Formic acid) and CH₃CN as eluents (Mobilephase A: water (0.2% Formic acid), Mobile phase B: CH₃CN, Detectorwavelength: 220 nm), followed by concentration (below 50° C.) to affordthe title compound.

Intermediate 22 2-Bromo-4-cyclobutoxy-1-fluorobenzene

To a soln. of 3-bromo-4-fluorophenol (50.0 g, 262 mmol) in DMF (400 mL)was added bromocyclobutane (38.9 g, 288 mmol), TBAI (48.3 g, 131 mmol)and Cs₂CO₃ (102 g, 314 mmol). The mixture was stirred at 90° C. for 12h. The reaction mixture was diluted with water (1 L) and extracted withthe mixture of PE:EtOAc=4:1 (3×1 L). The organic layer was concentratedin vacuo to give the crude product, which was purified by silica gelcolumn chromatography (PE) to give the title compound. ¹H-NMR (400 MHz,CDCl₃) ppm 6.97-7.03 (m, 2H) 6.70-6.73 (m, 1H) 4.53-4.60 (m, 1H)2.43-2.46 (m, 2H) 2.14-2.17 (m, 2H) 1.80-1.91 (m, 1H) 1.60-1.73 (m, 1H).

Intermediate 23 1-Bromo-5-cyclobutoxy-3-(difluoromethyl)-2-fluorobenzene

Step A. 3-Bromo-5-cyclobutoxy-2-fluorobenzaldehyde: To a soln. of2,2,6,6-tetramethyl-piperidine (3.46 g, 24.48 mmol) in THF (50 mL) wasadded 2.5 M nBuLi (9.8 mL, 24.48 mmol) dropwise at −78° C. under N₂.After 30 min, 2-bromo-4-cyclobutoxy-1-fluorobenzene (5.0 g, 20.4 mmol)in THF (15 mL) was added dropwise at −78° C. Then the mixture wasstirred at −78° C. for 1 h. DMF (2.237 g, 30.6 mmol) was added dropwiseat −78° C., and the mixture was stirred for another 1 h. The reactionwas quenched with satd. aq. NH₄Cl soln. (10 mL), and the mixture wasextracted with EtOAc (3×50 mL) and water (30 mL). The organic layer wasdried with anhyd. Na₂SO₄ and concentrated in vacuo. The residue waspurified via silica gel chromatography (PE) to afford the titlecompound.

Step B. 1-Bromo-5-cyclobutoxy-3-(difluoromethyl)-2-fluorobenzene: To asoln. of 3-bromo-5-cyclobutoxy-2-fluorobenzaldehyde (1.00 g, 3.66 mmol)in DCM (20 mL), was added DAST (2.4 mL, 18.16 mmol) dropwise at 0° C.Then the mixture was stirred at 19° C. for 2 h. The mixture was quenchedwith water (5 mL) and extracted with DCM (20 mL×2) and water (15 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified via silica gel chromatography (PE) to afford thetitle compound. ¹H-NMR (400 MHz, CDCl₃) δ 1.66-1.77 (m, 1H) 1.83-1.95(m, 1H) 2.09-2.24 (m, 2H) 2.39-2.53 (m, 2H) 4.55-4.66 (m, 1H) 6.67-7.01(m, 2H) 7.10 (br. s., 1H).

Intermediate 24 1-Bromo-2-fluoro-3-methoxy-5-(trifluoromethoxy)benzene

Step A. 2-fluoro-5-(trifluoromethoxy)phenol: To a stirred soln. of(2-fluoro-5-(trifluoro-methoxy)phenyl)boronic acid (13.40 g, 60 mmol) inanhyd. EtOH (20 mL) was added dropwise 30% H₂O₂ (10.2 mL, 90 mmol) at0-5° C., and the reaction mixture was stirred for 3 h. The reaction wasquenched with a satd. soln. of Na₂S₂O₃, and concentrated in vacuo. Theresulting residue was dissolved in DCM (30 mL), and the soln. was washedwith brine (10 mL×2). The organic layer was concentrated in vacuo togive the title compound.

Step B. 1-Fluoro-2-methoxy-4-(trifluoromethoxy)benzene: To a stirredsuspension of 2-fluoro-5-(trifluoromethoxy)phenol (5.00 g, 25 mmol) andK₂CO₃ (5.20 g, 38 mmol) in DMF (10 mL) was added MeI dropwise at rt. Thereaction mixture was stirred for 18 h at rt, then poured into water (100mL), and extracted with DCM (20 mL×3). The organic layer was washed withbrine (20 mL) and concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (PE:EtOAc=10:1) to give the titlecompound.

Step C. 1-Bromo-2-fluoro-3-methoxy-5-(trifluoromethoxy)benzene: To asoln. of 2,2,6,6-tetramethylpiperidine (3.40 g, 24 mmol) in anhyd. THF(30 mL) was added dropwise 2.5 M n-BuLi (9.0 mL, 23 mmol) at −78° C.under N₂. After the addition, the reaction mixture was stirred at −75°C. for 30 minutes. Then a soln. of1-fluoro-2-methoxy-4-(trifluoromethoxy)-benzene (4.0 g, 19 mmol) in THF(10 mL) was added dropwise to the reaction mixture at −78° C. After theaddition, the reaction mixture was stirred for 2 h at −78° C., and Br₂(3.70 g, 23 mmol) was added dropwise to the reaction mixture whilemaintaining at −78° C. The reaction mixture was allowed to stir for 1 hat −75° C., and the reaction was quenched with satd. aq. NH₄Cl (5 mL).The mixture was washed with brine (20 mL), and the organic layer wasconcentrated in vacuo. The resulting residue was purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and ACN as eluents(Mobile phase A: water (0.2% Formic acid), Mobile phase B: ACN,Detective wavelength: 220 nm) followed by concentration in vacuo toobtain the title compound. ¹H NMR (400 MHz, CDCl₃) ppm: 7.04 (br. s.,1H) 6.79 (d, J=4.30 Hz, 1H) 3.91 (s, 3H).

Intermediate 252-(3-Bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methylpyridine

Step A.2-(3-Bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methyl-3-nitropyridine:A mixture of 2-chloro-5-methyl-3-nitropyridine (300 mg, 1.74 mmol) and3-bromo-5-(difluoromethyl)-4-fluorophenol (503 mg, 2.09 mmol) and Cs₂CO₃(850 mg, 2.61 mmol) in DMF (10 mL) was stirred at 15° C. for 2 h. Themixture was diluted with water (20 mL), and extracted with PE:EtOAc(1:1, 2×10 mL). The organic layer was collected, washed with brine,dried over anhyd. Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel column chromatography (PE:EtOAc from100:1 to 1:1) to afford the title compound. m/z 377.1 [M+H]⁺

Step B.2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methylpyridin-3-amine:A mixture of2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methyl-3-nitropyridine(550 mg, 1.46 mmol), zinc (286 mg, 4.38 mmol), and NH₄Cl (390 mg, 7.29mmol) in a mixture of MeOH (10 ml) and water (1 mL) was heated at 60° C.for 3 h. The suspension was diluted with DCM (20 ml) and filteredthrough silica gel. The filtrate was concentrated in vacuo, and themixture was diluted with water (10 mL) and extracted with DCM (20 mL).The organic layer was collected, washed with brine, dried over anhyd.Na₂SO₄, filtered, then concentrated under in vacuo to afford the titlecompound. m/z=348.1 [M+H]⁺.

Step C. 2-(3-Bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methylpyridine:A mixture of2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methylpyridin-3-amine(500 mg, 1.44 mmol) and isopentyl nitrate (384 mg, 2.88 mmol) in THF (10mL) was heated under reflux for 2 h. After cooling to rt, the mixturewas diluted with water (20 mL), and extracted with EtOAc (15 mL×2). Theorganic layer was collected, washed with brine, dried over anhyd.Na₂SO₄, filtered, then concentrated in vacuo. The crude product waspurified by silica gel column chromatography (PE:EtOAc from 20:1 to10:1) to afford the title compound. m/z 333.1 [M+H]⁺.

Intermediate 26 2-(3-Bromo-4-fluoro-5-methoxyphenoxy)-5-methylthiazole

Step A. 3-Bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenol: To a stirredsoln. of 2,2,6,6-tetramethylpiperidine (2.5 g, 17.2 mmol) in anhyd. THF(30 mL) was added dropwise n-BuLi (7.0 mL, 17.2 mmol) below −75° C.under N₂. The reaction mixture was stirred for 30 min. Then a soln. of(3-bromo-4-fluorophenoxy) triisopropylsilane (5.0 g, 14.4 mmol) in THF(5 mL) was added dropwise to the reaction mixture below −75° C. Afterthe addition, the reaction mixture was stirred for 2 h maintaining at−75° C. Trimethyl borate (1.80 g, 17.2 mmol) was added dropwise to thereaction mixture below −75° C. Then the reaction mixture was stirred for1 h. The reaction mixture was warmed to rt to give a soln. of crudedimethyl (3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)boronate.Then, 30% NaOH (4 mL, 28.8 mmol)) was added to the soln. with stirringat rt. The reaction mixture was cooled in an ice-bath, and 30% H₂O₂ (3.3mL, 28.8 mmol) was added dropwise to the mixture. After the addition,the reaction was warmed to rt and stirred for 10 h. The reaction mixturewas acidified to pH˜4 with 3 N HCl and extracted with EtOAc (3×30 mL).The combined organic layers were washed with brine and concentrated invacuo. The residue was purified by silica gel chromatography (PE/EtOAc20:1) to give the title compound.

Step B. (3-Bromo-4-fluoro-5-methoxyphenoxy)triisopropylsilane: To astirred suspension of 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenol(3.3 g, 9 mmol) and K₂CO₃(1.50 g, 11 mmol) in DMF (10 mL), cooled by anice water bath, was added dropwise MeI (2.60 g, 18 mmol). After theaddition, the reaction mixture was stirred for 3 h at ˜16° C. Thereaction mixture was poured into water (100 mL) and extracted with PE(2×10 mL). The combined organic layers were washed with brine,concentrated in vacuo to give crude product.

Step C. 3-Bromo-4-fluoro-5-methoxyphenol: To a stirred soln. of(3-bromo-4-fluoro-5-methoxyphenoxy) triisopropylsilane (3.10 g, 8.2mmol) in THF (10 mL) was added dropwise 1 M TBAF (9.8 mL, 9.8 mmol) at˜16° C. The reaction mixture was stirred at ˜16° C. for 3 h andconcentrated in vacuo. The resulting residue was dissolved in DCM (20mL), and the organic layer was separated and washed with brine. Theorganic layer was then concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (PE:EtOAc=10:1) to give the titlecompound.

Step D. 2-(3-Bromo-4-fluoro-5-methoxyphenoxy)-5-methylthiazole: To asoln. of 3-bromo-4-fluoro-5-methoxyphenol (663 mg, 3 mmol) and2-bromo-5-methylthiazole (587 mg, 3.3 mmol) in NMP (5 mL) was addedCs₂CO₃ (1.20 g, 3.6 mmol) in one portion. The reaction vessel was sealedand heated by microwave irradiation at 150° C. for 3 h. The reactionmixture was poured into cold water (50 mL) and extracted with DCM (3×10mL). The combined layers were combined and washed with brine, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by silicagel chromatography (PE:EtOAc=10:1) to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.06 (dd, J=4.70, 2.74 Hz, 1H) 6.82-6.92 (m, 2H)3.89 (s, 3H) 2.38 (s, 3H).

Intermediate 27 2-Bromo-4-cyclobutoxy benzonitrile

Step A. 2-Bromo-4-hydroxybenzonitrile: To a soln. of2-bromo-4-methoxybenzonitrile (1 g, 4.72 mmol) in MeCN (40 mL) was addedNaI (2.12 g, 14.15 mmol) and TMSCl (1.54 g, 14.15 mmol). Then themixture was stirred at 80° C. overnight. Then the mixture wasconcentrated in vacuo and poured into water basified with Na₂CO₃. Themixture was extracted with EtOAc. The aq. layer was acidified with HCland extracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), and concentrated in vacuo to give the title compound.

Step B. 2-Bromo-4-cyclobutoxybenzonitrile: To a soln. of2-bromo-4-hydroxybenzonitrile (110 mg, 0.56) in DMF (40 mL) was addedbromocyclobutane (150 mg, 1.11 mmol), Bu₄NI (205 mg, 0.56 mmol) andCs₂CO₃ (181 mg, 0.56 mmol). The reaction mixture was stirred at 90° C.overnight. The mixture was washed with water, extracted with EtOAc, andthe separated organic layer was washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by silica gelchromatography (PE:EA=20:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ: 7.54 (d, J=8.61 Hz, 1H), 7.08 (d, J=1.96 Hz, 1H), 6.81 (dd,J=8.80, 2.15 Hz, 1H), 4.67 (t. J=7.24 Hz, 1H), 2.40-2.54 (m, 2H), 2.19(ddd, J=9.88, 7.53, 2.54 Hz, 2H), 1.91 (d, J=10.56 Hz, 1H), 1.66-1.81(m, 1H).

Intermediate 28 1-bromo-5-cyclobutoxy-2-fluoro-4-methoxybenzene

Step A. 1-cyclobutoxy-4-fluoro-2-methoxybenzene, To a solution ofcompound 4-fluoro-2-methoxyphenol (1 g, 7 mmol) and bromocyclobutane(1.13 g, 8.4 mmol) in DMF (5 mL) was added Cs₂CO₃ (3.4 g, 10.6 mmol) atrt. The mixture was stirred at 80° C. for 12 h. The mixture wasconcentrated in vacuo and extracted with EtOAc (40 mL). The organiclayer was concentrated in vacuo, and the crude product was purified bysilica gel column (PE:EA=100:1) to give the title compound.

Step B. 1-bromo-5-cyclobutoxy-2-fluoro-4-methoxybenzene: To a solutionof compound 1-cyclobutoxy-4-fluoro-2-methoxybenzene (1 g, 5.2 mmol) inMeCN (10 mL) was added NBS (1.02 g, 5.8 mmol) at 0° C. The mixture wasstirred at rt for 12 h. Water (50 mL) was added to the mixture, and themixture was extracted with EtOAc (40 mL). The organic layer wasconcentrated in vacuo, and the crude product was purified by silica gelchromatography (PE:EA=100:1) to give the title compound.

Intermediate 292-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methylthiazole

Step A. 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde: To astirred solution of 2,2,6,6-tetramethylpiperidine (18.06 g, 0.13 mol) inTHF (250 mL) was added n-BuLi (2.5 M, 51.1 mL, 0.13 mol) dropwise at−78° C. over 0.5 h. The mixture was stirred at 0° C. for 0.5 h. Then asolution of 3-bromo-4-fluorophenoxy)triisopropylsilane (37.0 g, 0.11mmol) in THF (300 mL) was added to the above mixture dropwise at −78° C.over 0.5 h. The mixture was stirred for 1 h, and DMF (15.57 g, 213 mmol)was added. The mixture was diluted with water (300 mL), and extractedwith EtOAc (2×100 mL). The organic layer was separated, washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by silica gel column chromatography(PE:EtOAc from 20:1 to 1:1) to afford3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde and3-bromo-2-fluoro-5-hydroxybenzaldehyde.

Step B. 3-bromo-5-(difluoromethyl)-4-fluorophenoxy)triisopropylsilane:To a stirred solution of3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde (22.00 g, 58.60mmol) in DCM (200 mL) was added dropwise DAST (11.62 ml, 88.00 mmol) at0° C. The resulting mixture was warmed to rt for 2 h. The mixture waspouring into diluted NaHCO₃ solution until the pH was 5. Water (100 mL)was added and the mixture was extracted with DCM (100 mL). The organiclayer was separated, washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (PE:EtOAc 20:1 to 5:1) to afford the titlecompound.

Step C: 3-bromo-5-(difluoromethyl)-4-fluorophenol: A mixture of(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)triisopropylsilane (10.0 g,25.2 mmol) and TBAF (7.90 g, 30.2 mmol) in THF (50 mL) was stirred at15° C. for 2 h. The mixture was diluted with water (50 mL), andextracted with EtOAc (50 mL). The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography(PE:EtOAc from 10:1 to 3:1) to afford the title compound.

Step D. 2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-methylthiazole:A mixture of 2-bromo-5-methylthiazole (300 mg, 1.68 mmol),3-bromo-5-(difluoromethyl)-4-fluorophenol (487 mg, 2.02 mmol) and Cs₂CO₃(1.09 g, 3.37 mmol) in DMF (5 mL) was irradiated by microwave at 160° C.for 0.5 h. The mixture was diluted with water (20 mL), and extractedwith EtOAc (2×0 mL). The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was further purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and MeCN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detective wavelength: 220nm), followed by concentration (below 50° C.) to afford the titlecompound.

Intermediate 30 1-Bromo-5-cyclobutoxy-2-fluoro-3-methoxybenzene

Step A. 3-bromo-5-cyclobutoxy-2-fluorophenol: To a solution of TMP (5.9g, 41.6 mmol) in anhydrous THF (5 mL) was added dropwise 2.5 M n-BuLi(17 mL, 41.6 mmol) at between −78 and −75° C. under nitrogen. After theaddition the reaction mixture was stirred at −75° C. for 30 min. Then asolution of 2-bromo-4-cyclobutoxy-1-fluorobenzene (8.5 g, 34.6 mmol) inTHF (10 mL) was added dropwise to the reaction mixture at −75° C. Thereaction mixture was stirred for 1 h at −75° C. Then a solution oftrimethyl borate (4.3 g, 41.6 mmol) in THF (5 mL) was added dropwise tothe reaction mixture while maintaining at −75° C. After the addition,the reaction mixture was allowed to stir for 1 h at −75° C. Thenreaction mixture was allowed to warm to rt.

Then 30% aq. NaOH (11 mL, 68.7 mmol)) was added to the solution withstirring at rt. The reaction mixture cooled by ice-bath, and 30%hydrogen peroxide (8 mL, 68.7 mmol) was slowly added dropwise. Afteraddition, the reaction mixture was warmed to the rt and stirred for 10h.

The reaction mixture was acidified to pH˜4 with 3 N HCl and extractedwith EtOAc (30 mL×3).

The organic layer was washed with brine and concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE:EtOAc 20:1) togive the title compound.

Step B. 1-bromo-5-cyclobutoxy-2-fluoro-3-methoxybenzene: To a suspensionof 3-bromo-5-cyclobutoxy-2-fluorophenol (8.0 g, 30.6 mmol) and K₂CO₃(8.5 g, 61.2 mmol) in DMF (25 mL), cooled by an ice bath, was addeddropwise MeI (20.0 g, 141.0 mmol). After the addition, the reactionmixture was stirred for 12 h at rt. The reaction mixture was poured intocold water (100 mL) and extracted with DCM (30 mL×3). The organic layerwas rinsed with brine and concentrated in vacuo. The residue waspurified by reverse phase HPLC on a GILSON 281 instrument fitted with aPhenomenex Synergi C18 (250×21.2 mm×4 μm) using water (0.2% Formic acid)and MeCN as eluents (Mobile phase A: water (0.2% Formic acid), Mobilephase B: MeCN, Detective wavelength: 220 nm) followed by concentration(below 50° C.) to obtain the title compound. ¹H NMR (400 MHz, CDCl₃) δppm 6.47 (d, J=4.02 Hz, 1H) 6.39-6.45 (m, 1H) 4.56 (quin, J=7.15 Hz, 1H)3.85 (s, 3H) 2.39-2.51 (m, 2H) 2.07-2.21 (m, 2H) 1.87 (q, J=10.21 Hz,1H) 1.64-1.77 (m, 1H).

Intermediate 31Ethyl-2-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate

Step A.Tert-butyl-6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution of 6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (1.8 g,7.82 mmol) in DCM (30 mL) was added Boc₂O (2.0 mL, 8.61 mmol) in oneportion with stirring at −26° C. Then the reaction mixture was stirredat −26° C. for an additional 18 h. The reaction mixture was concentratedin vacuo to give the crude product which was purified by silica gelcolumn chromatography (PE/EtOAc 40:1-20:1) to give the title compound.

Step B.(E)-tert-butyl-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution of tert-butyl6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.2 g, 6.66mmol) in dry 1,4-dioxane (20 mL) was added tri-tert-butyl phosphoniumtetrafluoroborate (0.387 g, 1.333 mmol),N-cyclohexyl-N-methylcyclo-hexanamine (1.952 g, 9.99 mmol), and ethylacrylate (0.800 g, 8.00 mmol) with stirring at ˜26° C. The mixture wasdegassed for 5 min with N₂, and Pd₂(dba)₃ (203 mg, 0.221 mmol) wasadded. The mixture was stirred at 100° C. for 18 h under a N₂atmosphere. The mixture was cooled to rt and diluted with EtOAc (20 mL).The organic layer was filtered, and the filtrate was concentrated invacuo to give the residue which was purified by silica gelchromatography (PE:EtOAc=20:1 to 10:1) to afford the title compound.

Step C. Tert-butyl6-(2-(ethoxycarbonyl)cyclopropyl)-5-fluoro-3,4-dihydroiso-quinoline-2(1H)-carboxylateTo a solution of(E)-tert-butyl-6-(3-ethoxy-3-oxoprop-1-en-1-yl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(5.1 g, 14.60 mmol) and palladium acetate (0.328 g, 1.460 mmol) in dryDCM/ether (1:2, 450 mL) was added CH₂N₂ (117 mL, 58.4 mmol) in diethylether at 0° C. over a period of 2 h. Then the reaction mixture wasslowly warmed to rt and stirred for 18 h. The reaction was quenched byaddition of AcOH (10 mL). The resulting mixture was washed with water(200 mL) and brine (100 mL). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to give the crude product. The crude product waspurified by silica gel column chromatography (PE/EtOAc 30:1-10:1) togive tert-butyl6-(2-(ethoxycarbonyl)cyclopropyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate.¹H NMR (400 MHz CDCl₃) δ 6.82-6.73 (m, 2H), 4.51 (br. s., 2H), 4.16 (q,J=7.0 Hz, 2H), 3.61 (br. s., 2H), 2.77 (br. s., 2H), 2.63-2.58 (m, 1H),1.89-1.84 (m, 1H), 1.58-1.53 (m, 1H), 1.33-1.28 (m, 1H), 1.28-1.23 (m,3H). The two enantiomers were separated by SFC using the followingconditions: Instrument: MG-II, Column: Chiralpak AD 250×30 mm I.D., 5um, Mobile phase: Supercritical CO₂/A (0.1% NH;/H₂O)=85/15 at 60 mL/min,A=MeOH+HEP (1:1). Column Temp: 38° C. Nozzle Pressure: 100 Bar, NozzleTemp: 60° C. Evaporator Temp: 20° C., Trimmer Temp: 25° C. Wavelength:220 nm Peak 1 (ee 97.0% fast eluting) and Peak 2 (ee 97.7% slow eluting)were obtained from the racemate. (Peak1) ¹H NMR (400 MHz, CDCl₃) δ6.82-6.75 (m, 2H), 4.53 (br. s., 2H), 4.17 (d, J=7.0 Hz, 2H), 3.63 (br.s., 2H), 2.79 (br. s., 2H), 2.65-2.59 (m, 1H), 1.91-1.85 (m, 1H),1.60-1.56 (m, 1H), 1.48 (s, 9H), 1.36-1.30 (m, 1H), 1.30-1.26 (m, 3H);(Peak2) ¹H NMR (400 MHz, CDCl₃) δ 6.83-6.74 (m, 2H), 4.53 (br s., 2H),4.18 (q, J=7.2 Hz, 2H), 3.63 (br. s., 2H), 2.79 (br. s., 2H), 2.62 (t,J=9.8 Hz, 1H), 1.91-1.86 (m, 1H), 1.58 (d, J=4.3 Hz, 1H), 1.48 (s, 9H),1.35-1.31 (m, 1H), 1.30-1.26 (m, 3H)

Step E. Ethyl2-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-carboxylate.To a solution of tert-butyl6-(2-(ethoxycarbonyl)cyclopropyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(500 mg, 1.376 mmol) in DCM (6 mL) was added TFA (3 mL, 38.9 mmol)dropwise with stirring at −26° C. The solvent was removed in vacuo. Theresidue was purified by cation ion exchange column chromatography (1 MNH₃-MeOH) to afford the title compound.

Intermediate 32 2-(3-bromo-4-fluorophenoxy)pyrazine

To a stirred solution of 2-fluoropyrazine (1 g, 10.20 mmol) in DMSO (12mL) was added 3-bromo-4-fluorophenol (1.95 g, 10.21 mmol), andK₂CO₃(2.82 g, 20.39 mmol). The reaction mixture was stirred at 75° C.for 15 h. The mixture was filtered, and the filtrate was diluted withbrine (50 mL). The filtrate was extracted with EtOAc (2×100 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound. m/z 270.9 (M+2+H)⁺.

Intermediate 335-((1R,3R)-3-(benzyloxy)cyclobutoxy)-3-bromo-2-fluorobenzonitrile

Step A (3-bromo-4-fluorophenoxy)triisopropylsilane: TIPS-Cl (33.3 mL,157 mmol) was added to a stirred mixture of 3-bromo-4-fluorophenol (30g, 157 mmol) and imidazole (10.69 g, 157 mmol) in DMF (150 mL) at it,and the mixture was stirred at rt for 12 h. The mixture was diluted withEtOAc (300 mL), washed with water (2×800 mL), dried (Na₂SO₄), andfiltered, and the filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatography (PE) to give the title compound.

Step B. 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde: To asolution of 2,2,6,6-tetramethylpiperidine (4.64 g, 32.8 mmol) in THF (50mL) was added n-BuLi (13 mL, 32.5 mmol, 2.5 M in hexane) dropwise at−78° C. under N₂. After 30 min, the mixture was allowed to warm to 0° C.and stirred for 10 min. Then (3-bromo-4-fluorophenoxy)triisopropylsilane (10 g, 27.4 mmol) in THF (30 mL) was added dropwiseat −78° C., and the mixture was stirred at −78° C. for 1.5 h. DMF (3.00g, 41.0 mmol) was added, and the mixture was stirred at −78° C. for 40min. The reaction was quenched by the addition of satd. NH₄Cl solution(50 mL). Then the mixture was extracted with EtOAc (150 mL×2). Theorganic layer was washed with brine (50 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. The resulting residue was purified by silicagel chromatography (EtOAc:petroleum ether 1:100 to 1:50) to give thetitle compound.

Step C: 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde oxime:To a solution of 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde(7.60 g, 19.24 mmol) in EtOH (80 mL) was added hydroxylamine (2.54 g,38.5 mmol) (50% in water). The mixture was stirred at 80° C. for 5 h andcooled to rt. The mixture was poured onto water (100 mL), and themixture was stirred for 30 min. The mixture was concentrated in vacuo,and the residue was extracted with DCM (3×50 mL) and water (30 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (PE:EtOAc=50:1) toafford the title compound. m/z 390.0 [M+H]⁺.

Step D. 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzonitrile: To asolution of 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehydeoxime (7.30 g, 18.35 mmol) in DMF (80 mL) was added POCl₃ (7.03 g, 4.27mL, 45.9 mmol) dropwise at 0° C. The mixture was stirred at rt for 15 h.The mixture was poured into water (800 mL), and the mixture was stirredfor 1 h. The mixture was extracted with EtOAc (2×150 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (PE) to afford the title compound.

Step E: 3-bromo-2-fluoro-5-hydroxybenzonitrile. TBAF (10 mL, 10.00 mmol)(1 M in THF) was added to a stirred mixture of3-bromo-2-fluoro-5-((triisopropylsilyl)oxy) benzonitrile (4.0 g, 9.67mmol) in THF (20 mL) at rt. The mixture was stirred at rt 20° C. for 2h. The mixture was concentrated in vacuo, and the residue was dilutedwith EtOAc (30 mL) and washed with water (20 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (EtOAc: PE 1:2) to give the titlecompound.

Step F.5-((1r,3r)-3-(benzyloxy)cyclobutoxy)-3-bromo-2-fluorobenzonitrile. To asolution of 3-bromo-2-fluoro-5-hydroxybenzonitrile (1.00 g, 4.40 mmol),(1S,3S)-3-(benzyloxy)cyclobutanol (0.862 g, 4.84 mmol) and PPh₃ (1.730g, 6.60 mmol) in THF (15 mL) was added DIAD (1.197 ml. 6.16 mmol)dropwise with stirring at 0° C. under a N₂ atmosphere. After theaddition was complete, the reaction mixture was stirred at −70° C. foradditional 15 h under a N₂ atmosphere. The solvent was removed in vacuo.The resulting residue was purified via silica gel chromatography(PE:EtOAc=100:1 to 50:1) to afford the title compound. ¹HNMR 6 (CDCl₃,400 MHz, ppm): 7.29-7.41 (m, 5H) 7.22 (dd, J=5.40, 2.98 Hz, 1H)6.88-6.95 (m, 1H) 4.76-4.85 (m, 1H) 4.43-4.49 (m, 2H) 4.29-4.37 (m, 1H)2.49-2.60 (m, 2H) 2.36-2.46 (m, 2H).

Intermediate 342-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-fluoropyridine

Step A.2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-fluoro-3-nitropyridine.A mixture of 2-chloro-5-fluoro-3-nitropyridine (300 mg, 1.69 mmol) and3-bromo-5-(difluoromethyl)-4-fluorophenol (491 mg, 2.03 mmol), Cs₂CO₃(554 mg, 1.69 mmol) in DMF (10 mL) was stirred at 15° C. for 2 h. Themixture was diluted with water (20 mL), extracted with PE:EtOAc (1:1,2×10 mL). The organic layer was separated and washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography (DCM) to yield thetitle compound.

Step B:2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-fluoropyridin-3-amine.A mixture of2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-fluoro-3-nitro pyridine(600 mg, 1.574 mmol), zinc (309 mg, 4.72 mmol) and NH₄Cl (421 mg, 7.87mmol) in water (1 mL) and MeOH (10 mL) was heated at 60° C. for 6 h. Themixture was diluted with DCM (20 mL) and filtered through silica gel.The filtrate was concentrated in vacuo. Water (10 mL) was added to theresidue, and the mixture was extracted with DCM (20 mL). The organiclayer was separated, washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to afford the title compound.

Step C: 2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-fluoropyridine:A mixture of 2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)-5-fluoropyridin-3-amine (500 mg, 1.42 mmol) and isopentyl nitrate (379 mg, 2.85mmol) in THF (10 mL) was heated at 66° C. for 2 h. After cooling themixture to rt, the mixture was diluted with water (20 mL), and extractedwith EtOAc (2×15 mL). The organic layer was collected, washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography (PE:EtOAcfrom 20:1 to 10:1) to afford the title compound.

Intermediate 355-Iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile

Step A: 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile:To a solution of (4-methoxyphenyl)hydrazine hydrochloride (50 g, 286.32mmol) in EtOH (400 mL) was added Et₃N (31.87 g, 314.96 mmol), and themixture was stirred for 10 min. Then2-(1-ethoxy-ethylidene)malononitrile (38.98 g, 286.32 mmol) was addedportionwise. The reaction mixture was stirred at rt overnight. Then thereaction mixture was filtered, and the filtrate was extracted with EtOAc(3×200 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (DCM to MeOH:DCM=1:20) to give the title compound.

Step B. 5-Iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile.To a solution of5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (30 g,131.6 mmol) in CH₂I₂ (105.78 g, 394.74 mmol) was added isopentyl nitrite(46.18 g, 394.74 mmol) dropwise at 0° C. The reaction mixture wasstirred at 90° C. for 2 h. The precipitate was filtered off, washed withwater and extracted with DCM (3×100 mL). The extract was dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE:EA=4:1) to give the title compound.

Intermediate 36 2-bromo-6-fluoro-4-(trifluoromethoxy)benzonitrile

Step A. 1-bromo-2-fluoro-5-nitro-4-(trifluoromethoxy)benzene: To asolution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (5.00 g, 19.31mmol) in MeCN (20 mL) was added NO₂BF₄ (2.69 g, 20.27 mmol) in portionskeeping the temperature between −40 to −30° C. The mixture was stirredat between −40° C. to −30° C. for 2 h. Then the mixture was allowed towarm to rt and stirred for 18 h. The mixture was poured into ice, andextracted with EtOAc (3×30 mL). The combined organic layers were driedover Na₂SO₄, filtrated and concentrated in vacuo. The residue waspurified on silica gel (PE:EtOAc=80:1 to 50:1) to afford the titlecompound.

Step B. 5-bromo-4-fluoro-2-(trifluoromethoxy)aniline: To a solution of1-bromo-2-fluoro-5-nitro-4-(trifluoromethoxy)benzene (2.00 g, 6.58 mmol)in MeOH (30 mL) and water (3 mL) was added Fe (1.837 g, 32.9 mmol) andNH₄Cl (1.760 g, 32.9 mmol). The mixture was stirred at 75° C. for 4 h.The mixture was filtered, and the solvent was removed in vacuo. Theresidue was extracted with DCM (3×30 mL) and water (3×30 mL). Theorganic layer was dried over Na₂SO₄, filtrated and concentrated invacuo. The residue was purified via silica gel chromatography (PE:EtOAc)to afford the title compound.

Step C: 3-bromo-5-(difluoromethyl)-4-fluorophenol: To a solution of5-bromo-4-fluoro-2-(trifluoromethoxy)aniline (520 mg, 1.898 mmol) in DMA(5 mL) was added dicyanozinc (134 mg, 1.139 mmol), zinc (10 mg, 0.153mmol), dppf (105 mg, 0.190 mmol) and Pd₂(dba)₃ (87 mg, 0.095 mmol). Thenthe reaction mixture was stirred and irradiated by microwave at 160° C.for 30 min. Water (50 mL) was added to the mixture, and the mixture wasextracted with EtOAc (20 mL×3). The organic layer was concentrated invacuo, and the crude product was purified by silica gel chromatography(PE/EtOAc=10:1 to 5:1) to give the title compound.

Step D. 3-amino-2-bromo-6-fluoro-4-(trifluoromethoxy)benzonitrile: To asolution of 5-amino-2-fluoro-4-(trifluoromethoxy)benzonitrile (370 mg,1.681 mmol) in DMF (10 mL), was added 1-bromopyrrolidine-2,5-dione (299mg, 1.681 mmol). The mixture was stirred at rt for 2 h. The reactionmixture was extracted with EtOAc (3×30 mL) and water (80 mL), and theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified via silica gel chromatography (PE:EtOAc=10:1)to afford the title compound.

Step E. 3-amino-2-bromo-6-fluoro-4-(trifluoromethoxy)benzonitrile: To asolution of 3-amino-2-bromo-6-fluoro-4-(trifluoromethoxy)benzonitrile(220 mg, 0.736 mmol) in THF (5 mL) was added isopentyl nitrite (172 mg,1.471 mmol). Then the mixture was stirred at 70° C. for 18 h. Themixture was concentrated in vacuo, and the resulting residue wasextracted with EtOAc (3×20 mL) and water (20 mL). The organic layer wasdried over Na₂SO₄, filtrated and concentrated. The residue was purifiedby silica gel PTLC (PE:EtOAC=10:1) to afford the title compound. ¹HNMR(CD₃OD, 400 MHz, ppm) δ: 7.68 (s, 1H) 7.51 (d, J=9.39 Hz, 1H).

Intermediate 37 1-bromo-2-chloro-5-cyclobutoxy-3-fluorobenzene

Step A. 1-bromo-3-cyclobutoxy-5-fluorobenzene. To a solution of3-bromo-5-fluorophenol (10.00 g, 52.4 mmol) in DMF (50 mL) was addedbromocyclobutane (14.14 g, 105 mmol), Bu₄NI (19.34 g, 52.4 mmol) andCs₂CO₃ (17.06 g, 52.4 mmol). Then the mixture was stirred at 90° C. for18 h. The mixture was diluted with water (400 mL) and extracted withEtOAc (3×80 mL). The organic layer was dried and concentrated in vacuo.The residue was purified via silica gel chromatography (PE) to affordthe title compound.

Step B. 1-bromo-2-chloro-5-cyclobutoxy-3-fluorobenzene. To a solution of1-bromo-3-cyclobutoxy-5-fluorobenzene (2.00 g, 8.16 mmol) in DMF (15 mL)was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (0.626 g, 2.69mmol). Then the mixture was stirred at 50° C. for 3 h. The mixture waspoured into water (30 mL) and extracted with EtOAc (3×30 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by reverse phase HPLC on a Shimadzu pump LC-8Ainstrument fitted with a SYNERGI (250×50×10 μm) using water (0.1% TFA)and MeCN as eluents (Mobile phase A: water (0.1% TFA), Mobile phase B:MeCN, Detective wavelength: 220 nm), followed by concentration (below50° C.) to afford the title compound. ¹HNMR (CDCl₃, 400 MHz, ppm) δ,1.66-1.76 (m, 1H) 1.89 (q, J=10.30 Hz, 1H) 2.10-2.22 (m, 2H) 2.40-2.51(m, 2H) 4.58 (quin. J=7.04 Hz, 1H) 6.60 (dd, J=10.17, 2.35 Hz, 1H) 6.90(br s, 1H).

Intermediate 38 3-bromo-5-cyclobutoxy-2-fluorobenzonitrile

Step A. 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)benzaldehyde. To asolution of 3-bromo-5-cyclobutoxy-2-fluorobenzaldehyde (Intermediate 23,step A, 1.00 g, 3.66 mmol) in EtOH (20 mL) was added NH₂OH (0.484 g,7.32 mmol), and the mixture was stirred at reflux for 5 h. After coolingto rt, the mixture was poured onto ice, and the mixture was stirred for30 min. The mixture was concentrated in vacuo, and the residue wasextracted with DCM (3×30 mL) and water (30 mL). The organic layer wasdried (Na₂SO₄) and concentrated in vacuo to afford the title compound.m/z 289.0 m/z [M+H]⁺.

Step B. 3-bromo-5-(difluoromethyl)-4-fluorophenoxy)triisopropylsilane.To a solution of (Z)-3-bromo-5-cyclobutoxy-2-fluorobenzaldehyde oxime(950 mg, 3.30 mmol) in DMF (5 mL) was added POCl₃ (1.77 g, 11.54 mmol)dropwise at 0° C. Then the mixture was stirred at 20° C. for 18 h. Themixture was poured into water and stirred for 1 h, and the solid thatformed was filtered. The solid was dissolved in DCM (30 mL), dried(Na₂SO₄) and concentrated in vacuo to afford the title compound. ¹HNMR(CDCl₃ 400 MHz, ppm), δ: 1.68-1.79 (m, 1H) 1.91 (q, J=10.30 Hz, 1H)2.09-2.23 (m, 2H) 2.39-2.52 (m, 2H) 4.58 (quin, J=6.95 Hz, 1H) 6.90-6.96(m, 1H) 7.24 (dd, J=5.09, 2.74 Hz, 1H).

Intermediate 39 2-bromo-4-((1r,3r)-3-methoxycyclobutoxy)benzonitrile

Step A. (1S,3S)-3-((tert-butyldimethylsilyl) oxy) cyclobutanol: To astirred solution of 3-((tert-butyldimethylsilyl)oxy)cyclobutanone (5.0g, 0.025 mol) in MeOH (60 mL) was added sodium tetrahydridoborate (1.5g, 0.040 mol) at 0° C. The resulting mixture was allowed to warm to rtand stirred for an additional 2 h. Then the mixture was cooled to rt,and the reaction was quenched with ice-water and saturated sodiumsulfate solution (10 mL). The mixture was filtered, and the filtrate wasconcentrated in vacuo to afford crude product. Water (100 mL) was addedto the crude product and the mixture was extracted with EtOAc (3×50 mL).The organic layer was dried (Na₂SO₄) and concentrated in vacuo to affordthe title compound.

Step B. 2-bromo-4-((1R,3R)-3-((tert-butyldimethylsilyl)oxy) cyclobutoxy)benzonitrile: To a stirred solution of(1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclobutanol (0.14 g, 0.69 mmol)in THF (8 mL) was added PPh₃ (0.25 g, 0.95 mmol),2-bromo-4-hydroxybenzonitrile (0.15 g, 0.76 mmol) at 0° C. DEAD (0.15 g,0.86 mmol) was added dropwise to the reaction mixture under a N₂atmosphere. The resulting mixture was stirred at 60° C. for 16 h. Themixture was cooled to rt and water (20 mL) was added. The mixture wasextracted with EtOAc (3×5 mL), and the organic layer was dried (Na₂SO₄),filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (PE/EtOAc=50:1) to give the title compound.

Step C. 2-bromo-4-((1R,3R)-3-hydroxycyclobutoxy)benzonitrile: To astirred solution of2-bromo-4-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)benzonitrile(120 mg, 0.31 mmol) in THF (5 mL) was added TBAF (110 mg, 0.42 mmol) atrt, and the mixture was stirred for 3 h under a N₂ atmosphere. Water (15mL) was added to the mixture, and the mixture was extracted with EtOAc(3×8 mL). The organic layer was dried (Na₂SO₄), and concentrated invacuo to afford crude product. The crude product was purified by silicagel chromatography (MeOH/DCM=1:50) to give the title compound.

Step D. 2-bromo-4-((1R,3R)-3-methoxycyclobutoxy)benzonitrile: To astirred solution of 2-bromo-4-((1R,3R)-3-hydroxycyclobutoxy)benzonitrile(65 mg, 0.24 mmol) in THF was added NaH (60% in mineral oil, 12 mg, 0.30mmol) at rt, and the mixture was stirred for 30 min. Then MeI (37 mg,0.26 mmol) was added, and the mixture was stirred for 16 h. Water (15mL) was added, and the mixture was extracted with EtOAc (3×10 mL). Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to affordcrude product. The crude product was purified by silica gelchromatography (PE/EtOAc=18:1 to 10:1 as eluent) to give the titlecompound. ¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.29-2.46 (m, 4H), 3.21 (s,3H), 4.00-4.13 (m, 1H), 4.71-4.82 (m, 1H), 6.68-6.80 (m, 1H), 6.95-7.02(m, 1H), 7.48 (d, J=8.60 Hz, 1H).

Intermediate 40 2-chloro-1-fluoro-3-iodo-5-(trifluoromethoxy)benzene

Step A. 2-fluoro-6-iodo-4-(trifluoromethoxy)aniline: To a solution of2-fluoro-4-(trifluoromethoxy)aniline (1.00 g, 5.13 mmol) in EtOH (20 mL)was added Ag₂SO₄ (1.598 g, 5.13 mmol) and I₂ (1.301 g, 5.13 mmol). Themixture was stirred at rt for 1 h, and the mixture was filtered, andconcentrated in vacuo. The residue was purified via silica gelchromatography (PE:EtOAc=80:1 to 40:1) to afford the title compound.

Step B. 2-chloro-1-fluoro-3-iodo-5-(trifluoromethoxy)benzene: To asolution of 2-fluoro-6-iodo-4-(trifluoromethoxy)aniline (300 mg, 0.935mmol) and CuCl₂ (251 mg, 1.869 mmol) in MeCN (20 mL) was addedtert-butyl nitrite (193 mg, 1.869 mmol) at 0° C. The mixture was stirredat rt for 2 h, and the mixture was concentrated in vacuo. Water (30 mL)was added, and the mixture was extracted with EtOAc (3×30 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified via silica gel chromatography (PE:EtOAc=50:1)to afford the title compound. ¹H NMR (CD₃OD, 400 MHz, ppm): 7.73 (br.s., 1H) 7.40 (dd, J=9.16, 1.88 Hz, 1H).

Intermediate 41 2-bromo-4-(cyclobutylmethyl)-1-fluorobenzene

Step A. 3-bromo-4-fluoro-N-methoxy-N-methylbenzamide. To a solution ofDIEA (4.78 ml, 27.4 mmol), 3-bromo-4-fluorobenzoic acid (2.0 g, 9.13mmol) and N,O-dimethylhydroxylamine hydrochloride (0.891 g, 9.13 mmol)in DMF (25 ml) was added HATU (3.47 g, 9.13 mmol) at 0° C., and themixture while stirring was allowed to gradually warm to rt. The mixturewas stirred at rt for 18 h. Water (100 mL) was added, and the mixturewas extracted with EtOAc (3×200 mL) and washed with brine (2×50 mL). Theorganic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.The resulting residue was purified by silica gel chromatography(PE:EtOAc=20:1˜5:1) to give the title compound. m/z 264.0 [M+H]⁺.

Step B: (3-bromo-4-fluorophenyl)(cyclobutyl)methanone: To a suspensionof magnesium (0.538 g, 22.13 mmol) in THF (20 ml) was added I₂ (0.028 g,0.111 mmol) at 40° C., and the mixture was stirred at 40° C. for 10 min.Then bromocyclobutane (2.99 g, 22.13 mmol) was added dropwise withstirring at 10° C. (under a N₂ atmosphere). After the addition wascomplete, the reaction mixture was stirred at 40° C. for 2 h. The abovesolution was added dropwise to a solution of3-bromo-4-fluoro-N-methoxy-N-methylbenzamide (2.9 g, 11.07 mmol) in THF(30 mL) at 0° C. (under a N₂ atmosphere). The mixture was stirred at rtfor 16 h. The reaction mixture was poured into ice water (20 mL), andthe mixture was extracted with EtOAc (30 mL×2). The combined organiclayer was washed with brine (20 mL×2), dried (Na₂SO₄), filtered andconcentrated in vacuo to give crude product. The crude product waspurified by silica gel column chromatography using (PE/DCM=100: 1-5:1)to give the title compound.

Step C. 2-bromo-4-(cyclobutylmethyl)-1-fluorobenzene. To a solution of(3-bromo-4-fluorophenyl)(cyclobutyl)methanone (125 mg, 0.486 mmol) inTFA (2 mL) was added triethylsilane (170 mg, 1.459 mmol) dropwise at 0°C. The mixture was stirred at 0° C. and gradually allowed to warm to rt,and the mixture was stirred for 16 h. The mixture was poured into aq.NaOH (30%, 50 mL), and the mixture was extracted with DCM (3×300 mL),washed with water (2×150 mL), and brine (2×150 mL). The organic layerwas dried (Na₂SO₄), filtered, and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatography(PE:EtOAc=200:1˜50:1) to give the crude product. ¹H NMR (400 MHz, CDCl₃)δ 8.12 (dd, J=2.0, 6.7 Hz, 1H), 7.84 (ddd, J=1.8, 4.7, 8.4 Hz, 1H), 7.19(t, J=8.2 Hz, 1H), 3.94 (quin, J=8.4 Hz, 1H), 2.47-2.25 (m, 4H),2.18-2.03 (m, 1H), 1.98-1.86 (m, 1H).

Intermediate 42 Ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A. (E)-ethyl 3-(6-chloroquinolin-2-yl)acrylate: To a solution of6-bromo-5-fluoroisoquinoline (210 mg, 0.929 mmol) in dry 1,4-dioxane (10mL) was added tri-tert-butylphosphonium tetrafluoroborate (51 mg, 0.176mmol), dicyclohexylamine (253 mg, 1.394 mmol), and ethyl acrylate (112mg, 1.115 mmol). The mixture was degassed for 5 min with N₂. ThenPd₂(dba)₃ (85 mg, 0.093 mmol) was added to the mixture, and the mixturewas stirred at 100° C. for 18 h under a N₂ atmosphere. The mixture wasdiluted with EtOAc (20 mL), and the mixture was filtered. The filtratewas concentrated in vacuo, and the resulting residue was purified bysilica gel chromatography (PE:EtOAc=20:1 to 3:1) to afford the titlecompound.

Step B. Ethyl 3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoateTo a solution of (E)-ethyl 3-(5-fluoroisoquinoline-6-yl)acrylate (220mg, 0.897 mmol) in MeOH (20 mL) was added platinum (IV) oxide (40 mg,0.176 mmol). The reaction mixture was stirred under a hydrogenatmosphere (50 psi) at 30° C. for 5 h. The reaction mixture was cooledto rt and filtered. The filtrate was concentrated in vacuo to give thetitle compound, which was used in the next step without furtherpurification. HNMR (400 MHz, CDCl₃) δ 7.02-6.91 (m, 1H), 6.73 (d, J=7.4Hz, 1H), 4.12 (q. J=7.0 Hz, 2H), 3.97 (s, 2H), 3.13 (t. J=6.1 Hz, 2H),2.92 (t, J=7.6 Hz, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H),1.24 (t, J=7.0 Hz, 3H).

Intermediate 435-((1r,3r)-3-(benzyloxy)cyclobutoxy)-1-bromo-2-fluoro-3-methoxybenzene

Step A. (3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)boronic acid:To a solution of 2,2,6,6-tetramethylpiperidine (6.10 g, 43.2 mmol) inTHF (150 ml) was added n-BuLi (2.5 M, 17.27 ml, 43.2 mmol) at −78° C.The mixture was stirred at −78° C. for 0.5 h, and then warmed to rt andstirred for 1 h. The mixture was extracted with EtOAc (100 mL×2), washedwith water (1 L), and dried (Na₂SO₄). The organic layer was concentratedin vacuo to give the crude product, which was used in the next stepwithout further purification.

Step B. 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenol: To a solutionof (3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)boronic acid(17.15 g, 43.8 mmol) in THF (150 ml) was added NaH (11.69 g, 88 mmol)(30%). Then H₂O₂ (9.94 g, 88 mmol) (30%) was added at 0° C. The mixturewas stirred at 15° C. for 16 h, then diluted with aqueous saturatedNa₂SO₃ (100 mL) and stirred for 0.5 h. The mixture was extracted withEtOAc (2×100 mL), washed with water (500 mL), dried (Na₂SO₄), filtered,concentrated in vacuo. The residue was purified by silica gel columnchromatography (PE:EtOAc=50:1 to 20:1) to give the title compound.

Step C. (3-bromo-4-fluoro-5-methoxyphenoxy)triisopropylsilane: To asolution of 3-bromo-2-fluoro-5-((triisopropylsilyl)oxy)phenol (8.0 g,22.02 mmol) and K₂CO₃ (6.09 g, 44.0 mmol) in DMF (50 ml) was added MeI(11.834 g, 83 mmol) at 0° C. The mixture was stirred at 15° C. for 16 h.Aq. saturated Na₂S₂O₃ (100 mL) was added, and the mixture was extractedwith EtOAc (50 mL×2), washed with water (500 mL), dried (Na₂SO₄),filtered, concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE:EtOAc=50:1 to 20:1) to give the titlecompound.

Step D. 3-bromo-4-fluoro-5-methoxyphenol: To a solution of(3-bromo-4-fluoro-5-methoxyphenoxy)triisopropylsilane (5.0 g, 13.25mmol) in THF (50 ml) was added TBAF (13.25 ml, 13.25 mmol, 1 M in THF).The mixture was stirred at 25° C. for 2 h. Water (100 mL) was added, andthe mixture was extracted with EtOAc (2×50 mL). The organic layer waswashed with water (200 mL), dried (Na₂SO₄), and concentrated in vacuo.The residue was purified by silica gel column chromatography(PE:EtOAc=10:1 to 5:1) to give the title compound.

Step E. 5-((1R,3R)-3-(benzyloxy)cyclobutoxy)-1-bromo-2-fluoro-3-methoxybenzene: To a stirred solution of 3-bromo-4-fluoro-5-methoxyphenol(0.546 g, 2.469 mmol), (1S,3S)-3-(benzyl-oxy)cyclobutanol (0.4 g, 2.244mmol) and PPh₃ (0.883 g, 3.37 mmol) in THF (15 mL) was added DEAD (0.569mL, 3.59 mmol) dropwise at 0° C. Then the reaction mixture was placedunder a nitrogen atmosphere and stirred at 80° C. for 15 h. The solventwas removed in vacuo, and the resulting residue was purified by silicagel chromatography (PE/EtOAc=20:1 to 10:1) to give the title compound.¹H NMR (400 MHz, CDCl₃) ppm δ 2.38-2.48 (m, 2H) 2.48-2.59 (m, 2H) 3.87(s. 3H) 4.30-4.44) (m, 1H) 4.75-4.88 (m, 1H) 6.42 (dd, J=6.65, 2.64 Hz,1H) 6.44-6.47 (m, 1H) 7.30-7.42 (m, 5H).

Intermediate 44 3-bromo-2-fluoro-5-(trifluoromethoxy)benzonitrile

Step A. 1-bromo-2-fluoro-4-nitro-5-(trifluoromethoxy)benzene: To asolution of 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (10.0 g, 38.6mmol) in CH₃CN (150 mL) was added nitronium tetrafluorborate (5.38 g,40.5 mmol) at 0° C., and the mixture was stirred at 0-18° C. for 16 h.The mixture was poured into water (50 mL) and extracted with EtOAc (200mL×3). The organic layer was washed with water (150 mL×2) and brine (150mL×2), dried (Na₂SO₄), and filtered. The filtrate was concentrated invacuo, and the resulting residue was purified by silica gelchromatography (PE:EtOAc=20:1˜5:1) to give the title compound.

Step B. 4-bromo-5-fluoro-2-(trifluoromethoxy)aniline: To a stirredsolution of 1-bromo-2-fluoro-4-nitro-5-(trifluoromethoxy)benzene (4.0 g,13.16 mmol) in MeOH (20 mL) and water (2 mL) was added NH₄Cl (7.04 g,132 mmol) and iron (2.204 g, 39.5 mmol). The mixture was stirred at 50°C. for 18 h. The mixture was extracted with EtOAc (2×50 mL) and water(2×30 mL), and the organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silia gelchromatography (PE:EtOAc=10:1) to give the title compound.

Step C. 4-amino-3-bromo-2-fluoro-5-(trifluoromethoxy)benzonitrile. To astirred solution of 4-amino-2-fluoro-5-(trifluoromethoxy)benzonitrile(0.76 g, 3.45 mmol) in CH₃CN (30 mL) was added NBS (0.615 g, 3.45 mmol),and the mixture was stirred at rt for 2 h. The mixture was diluted withwater (60 mL) and extracted with EtOAc (2×50 mL). The organic layer wasdried (Na₂SO₄) and concentrated in vacuo. The residue was purified bysilia gel chromatography (PE:EtOAc=30:1) to give the title compound.

Step D. 3-bromo-2-fluoro-5-(trifluoromethoxy)benzonitrile: To a stirredsolution of 2-amino-5-bromo-6-fluoro-3-(trifluoromethoxy)benzonitrile(330 mg, 1.104 mmol) in THF (10 mL) was added isopentyl nitrite (388 mg,3.31 mmol), and the mixture was stirred at 50° C. for 24 h. The mixturewas washed with water (2×10 mL) and extracted with EtOAc (2×30 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by silica gel PTLC (PE:EtOAc=10:1) to give thetitle compound.

Intermediate 45 methyl3-(1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A-6-bromo-3,4-dihydroisoquinoline: To a solution of6-bromo-1,2,3,4-tetrahydro-iso-quinoline (15.00 g, 71.1 mmol) in DCM(160 mL) was added activated MnO₂ (77.84 g, 859.7 mmol). The mixture wasstirred for 18 h at rt and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel chromatography(PE:EtOAc=20:1 to 5:1) to afford the title compound.

Step B-6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline: To a solution of6-bromo-3,4-dihydroisoquinoline (2.50 g, 11.9 mmol) in dry THF (50 ml)was added BF₃.Et₂O (9.0 ml, 71.0 mmol) at −78° C. in a N₂ atmosphere.After stirring for 5 min at −78° C., MeMgBr (4.26 g, 35.7 mmol) wasadded. The mixture was warmed to rt and stirred 18 h. The mixture wascooled to 0° C., and water was added to quench the reaction. The mixturewas extracted with EtOAc (100 mL×2). The organic layer was washed withbrine, dried (Na₂SO₄), and concentrated in vacuo to afford the titlecompound, which was used in the next step without further purification.

Step C. tert-butyl6-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate: To asolution of 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (1.50 g,6.63 mmol) in DCM (15 ml) was added TEA (1.8 ml, 13.2 mmol), followed by(Boc)₂O (2.2 g, 9.95 mmol). The mixture was stirred for 1 h at rt, andthe mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography (PE:EtOAc=30:1) to afford the title compound.

Step D. (E)-tert-butyl6-(3-methoxy-3-oxoprop-1-en-1-yl)-1-methyl-3,4-dihydro-isoquinoline-2(1H)-carboxylate:To a solution of tert-butyl6-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.50 g, 4.60mmol) in dioxane (15 mL) was added N,N-dicyclohexylmethylamine (1.34 g,6.86 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.13 g, 0.45mmol). The final mixture was degassed for 5 min with N₂. Then Pd₂(dba)₃(0.21 g, 0.229 mmol) and methyl acrylate (1.98 g, 23.00 mmol) wereadded. The final mixture was heated to 110° C. and stirred overnight ina N₂ atmosphere. The mixture was diluted with EtOAc (20 mL), filtered,and the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography (PE:EA=40:1 to 20:1) to afford the titlecompound. m/z 317.0 [M−16]⁺.

Step E tert-butyl6-(3-methoxy-3-oxopropyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate:To a solution of (E)-tert-butyl6-(3-methoxy-3-oxoprop-1-en-1-yl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(700 mg, 2.112 mmol) in MeOH (15 ml) was added Pd—C (70 mg, 0.66 mmol).The mixture was stirred overnight at 22° C. in a H₂ atmosphere (45 PSI).The mixture was filtered, and the filtrate was concentrated in vacuo toafford the title compound.

Step F. methyl3-(1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate: To a solutionoftert-butyl-6-(3-methoxy-3-oxoproropyl)-1-methyl-3,4-dihydro-iso-quinoline-2(1H)-carboxylate(350 mg, 1.05 mmol) in DCM (10 mL) was added HCl (4.0 M dioxanesolution, 3 mL). The mixture was stirred for 1 h at rt, and concentratedin vacuo. The residue was dissolved in MeOH (10 mL), and Cs₂CO₃ wasadded to adjust the pH to pH 8-9. Then the mixture was concentrated invacuo to afford the title compound, which was used in the next stepwithout further purification.

Intermediate 46 tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step A. (E)-tert-butyl6-(4-ethoxy-4-oxobut-2-en-2-yl)-3,4-dihydroisoquinoline-2(1H)-Carboxylate:To a solution of tert-butyl6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.0 g, 6.41 mmol) and(E)-ethyl but-2-enoate (1.462 g, 12.81 mmol) in dioxane (20 ml) wasadded tri-terbutylphosphonium tetrafluoroborate (0.186 g, 0.641 mmol)and Pd₂(dba)₃ (0.117 g, 0.128 mmol) followed by the addition ofN-cyclohexyl-N-methylcyclohexanamine (1.502 g, 7.69 mmol). The reactionwas stirred at 100° C. under a N₂ atmosphere for 12 h. The reactionmixture was partitioned between EtOAc (50 mL) and water (50 mL), and theorganic layer was washed with brine (50 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by silica gelchromatography (PE/EtOAc 30:1 to 10:1) to give the title compound.

Step B. tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate:To a mixture of (E)-tert-butyl6-(4-ethoxy-4-oxobut-2-en-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(400 mg, 1.158 mmol) in MeOH (10 ml) was added Pd—C (40 mg, 0.038 mmol),and the mixture was stirred at rt under a H₂ atmosphere (30 psi) for 50min. The mixture was filtered and concentrated in vacuo to afford thetitle compound. m/z 348.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.05 (s, 1H)7.00 (s, 1H) 4.54 (s, 2H) 4.09 (q, J=7.04 Hz, 2H) 3.64 (br. s., 2H) 3.24(dq, J=14.38, 7.08 Hz, 1H) 2.81 (br. s., 2H) 2.49-2.63 (m, 2H) 1.49 (s,9H) 1.29 (d, J=7.04 Hz, 3H) 1.20 (t, J=7.24 Hz, 3H).

Step C. tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate:Tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(350 mg) was purified by SFC(Column: Chiral Pak WHELK-O1, 5 μm, DaicelChemical Industries, Ltd 250×30 mm I.D. Mobile phase A: SupercriticalCO₂, Mobile phase B: EtOH (contained 0.1% ETOA), A:B=75:25 at 60 mL/min,Column Temp: 38° C., Wavelength: 220 nm, Nozzle Pressure: 100 Bar NozzleTemp: 60° C.) to afford tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydro-isoquinoline-2(1H)-carboxylateand tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-di-hydroisoquinoline-2(1H)-carboxylate.m/z 348.2 [M+H]⁺.

Intermediate 47 ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoatehydrochloride

Step A. tert-butyl6-(3-ethoxy-3-oxopropyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate:To a solution of ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (Intermediate7, 1.0 g, 3.98 mmol) in DCM (20 mL) were added Et₃N (0.6 mL, 4.30 mmol)and BOC₂O (1.1 mL, 4.74 mmol) with stirring at 0° C. (under a N₂atmosphere). The mixture was stirred at −26° C. overnight (˜18 h). Thesolvent was evaporated in vacuo, and the residue was purified by silicagel column chromatography (PE/EtOAc=20:1˜5:1) to give the titlecompound.

Step B. tert-butyl6-(3-ethoxy-2-methyl-3-oxopropyl)-5-fluoro-3,4-dihydro-isoquinoline-2(1H)-carboxylate:To a solution of tert-butyl6-(3-ethoxy-3-oxopropyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.3 g, 0.854 mmol) in anhydrous THF (10mL) with stirring at −78° C. was added KHMDS (1.3 mL, 1.300 mmol) in THFdropwise. The mixture was stirred at −78° C. for 30 min, and MeI (0.182g, 1.281 mmol) was added. The mixture was stirred for an additional 30min at −78° C., and the mixture was gradually warmed to rt for 18 h. Thereaction was quenched with water (10 mL), and the mixture was extractedwith EtOAc (2×20 mL). The organic phase was concentrated in vacuo togive crude product, which was purified by silica gel columnchromatography (EtOAc/PE 1:20-1:10) to give the title compound.

Step C. tert-butyl ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-propanoate: Toa solution of tert-butyl6-(3-ethoxy-2-methyl-3-oxopropyl)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(500 mg, 1.368 mmol) in dioxane (10 mL) was added a solution of 4 M HClin dioxane (5 mL), and the mixture was stirred at 24° C. for 18 h. Themixture was concentrated in vacuo to give the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 6.92 (t, J=7.63 Hz, 1H) 6.71 (d, J=8.22 Hz, 1H)4.06-4.12 (m, 2H) 3.96 (s, 2H) 3.12 (t, J=6.06 Hz, 2H) 2.96 (d, J=6.65Hz, 1H) 2.72 (br. s., 4H) 1.16-1.23 (m, 6H).

Intermediate 48 ethyl3-(5-fluoro-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A. 3-bromo-2-fluoro-4-methylbenzaldehyde. To a stirred solution of2-bromo-1-fluoro-3-methylbenzene (9.0 g, 47.6 mmol) in THF (150 mL) wasadded LDA (26.2 ml, 52.4 mmol) at −70° C. under a nitrogen atmosphere.The mixture was stirred for 1 h at −70° C., then DMF (4.5 g, 61.6 mmol)was added to the mixture. The mixture was allowed to warm to rt andstirred for 2 h. The reaction was quenched by addition of NH₄Cl solution(10 mL) and extracted with EtOAc (2×30 mL). The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel column chromatography (PE:EtOAc=20:1)to give the title compound.

Step B. (E)-methyl 3-(3-bromo-2-fluoro-4-methylphenyl)acrylate: To astirred solution of ethyl 2-(diethoxyphosphoryl)acetate (5.34 g, 23.82mmol) in THF (80 mL) was added NaH (1.0 g. 25.00 mmol). The resultingsolution was stirred at rt for 30 min. Then3-bromo-2-fluoro-4-methylbenzaldehyde (4.7 g, 21.66 mmol)) in THF (20mL) was added dropwise, and the mixture was stirred at rt for 2 h. Thereaction was quenched with NH₄Cl solution (5 mL), the resulting mixturewas extracted with EtOAc (100 mL×2). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel column chromatography (EtOAc:PE=1:15)to give the title compound.

Step C. (E)-3-(3-bromo-2-fluoro-4-methylphenyl)acrylic acid: To asolution of (E)-methyl 3-(3-bromo-2-fluoro-4-methylphenyl)acrylate (12.0g, 43.9 mmol) in THF (20 ml), MeOH (20 ml) and water (10 ml) was addedLiOH hydrate (3.69 g, 88 mmol). The mixture was stirred at 15° C. for 16h. The mixture was diluted with water (200 mL) and aqueous HCl (6N, 15mL) to adjust the pH to ˜4. The mixture was then extracted with EtOAc(2×100 mL), and the organic layer was washed with water (200 mL), driedover anhydrous Na₂SO₄, and concentrated in vacuo to give the crude titlecompound, which was used in next step without further purification.

Step D (E)-3-(3-bromo-2-fluoro-4-methylphenyl)acryloyl chloride: To asolution of (E)-3-(3-bromo-2-fluoro-4-methylphenyl)acrylic acid (4.5 g,16.50 mmol) in THF (30 mL) was added oxalyl chloride (2.304 g, 18.15mmol) and DMF (0.005 mL). The mixture was stirred at 18° C. for 2 h. Themixture was concentrated in vacuo to give the crude title compound,which was used in next step without further purification.

Step E. (E)-3-(3-bromo-2-fluoro-4-methylphenyl)acryloyl azide: To asolution of sodium azide (1.44 g, 22.15 mmol) in dioxane (8 mL) andwater (5 mL) was added (E)-3-(3-bromo-2-fluoro-4-methylphenyl)acryloylchloride (4.58 g, 16.50 mmol) in dioxane (10 mL) dropwise at 0° C. Themixture was stirred at 0° C. for 1 h, and water (100 mL) was added. Themixture was extracted with diethyl ether (3×30 mL), and organic layerwas washed with sat. aqueous of NaHCO₃ (2×30 ml) and brine (50 mL).dried over Na₂SO₄, and filtered. The organic layer was concentrated invacuo at a temperature of less than 40° C. behind a protective screen toafford the title compound.

Step F. 6-bromo-5-fluoro-7-methylisoquinolin-1(2H)-one: A solution of(E)-3-(3-bromo-2-fluoro-4-methylphenyl)acryloyl azide (4.69 g, 16.51mmol) in diphenyl ether (20 ml) was stirred at 250° C. for 3 h. Themixture was cooled to 20° C. and diluted with cyclohexane (40 mL). Theprecipitate was filtered and dried to give the title compound. m/z 255.9(M+H)⁺.

Step G. 6-bromo-1-chloro-5-fluoro-7-methylisoquinoline:6-bromo-5-fluoro-7-methyl-isoquinolin-1(2H)-one (0.65 g, 2.54 mmol) wasdissolved in POCl₃ (10.29 ml, 110 mmol), and the mixture was stirred at110° C. for 2 h. The reaction mixture was concentrated in vacuo, and theconcentrate was poured into water (20 mL). The water layer was extractedwith EtOAc (2×30 mL), and the organic layer was washed with aqueoussaturated NaHCO₃ solution. The organic layer was washed with brine (20mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo to givecrude product. The crude product was purified by silica gel columnchromatography (PE/EtOAc 10:1) to give the title compound. m/z 276.0(M+H)⁺.

Step H. 6-bromo-5-fluoro-7-methylisoquinoline. To a solution of6-bromo-1-chloro-5-fluoro-7-methylisoquinoline (350 mg, 1.275 mmol) inAcOH (5 ml) and hydrochloric acid. 37% (I ml) was added tin (454 mg,3.82 mmol). The mixture was stirred at 60° C. for 0.5 h. The mixture wasdiluted with water (100 mL). and the mixture was extracted with EtOAc(2×50 mL). The organic layer was washed with water (200 mL), dried overanhydrous Na₂SO₄, filtered, concentrated in vacuo. and the residue waspurified by silica column chromatography (PE:EtOAc=50:1 to 20:1) to givethe title compound. m/z 240.1 [M+H]⁺.

Step I. (E)-ethyl 3-(5-fluoro-7-methylisoquinolin-6-yl)acrylate. To asolution of 6-bromo-5-fluoro-7-methylisoquinoline (180 mg, 0.750 mmol)in dry 1,4-dioxane (10 ml) was added tri-tert-butylphosphoniumtetrafluoroborate (22 mg, 0.076 mmol), ethyl acrylate (120 mg, 1.2 mmol)and N-cyclohexyl-N-methylcyclohexanamine (439 mg, 2.249 mmol). Then themixture was degassed for 5 min with N₂, and Pd₂(dba)₃ (137 mg, 0.150mmol) was added to the mixture. The mixture was heated to 100° C. andstirred for 18 h in a N₂ atmosphere. The mixture was diluted with water(100 mL) and extracted with EtOAc (2×50 mL). The organic layer waswashed with water (200 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE:EtOAc=50:1 to 20:1) to give the title compound. m/z260.3 [M+H]⁺.

Step J. ethyl3-(5-fluoro-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate. To asolution of (E)-ethyl 3-(5-fluoro-7-methylisoquinolin-6-yl)acrylate (0.2g, 0.771 mmol) in EtOH (15 ml) was added platinum (IV) oxide (0.035 g,0.154 mmol). The reaction mixture was stirred under a hydrogenatomosphere (50 PSI) at 50° C. for 5 h. The mixture was filtered, andthe filtrate was concentrated in vacuo to give the title compound. m/z266.1 [M+H]⁺.

Intermediate 49 ethyl3-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A. 2-(3-bromo-4-fluorophenyl)acetamide: To a solution of2-(3-bromo-4-fluorophenyl)-acetic acid (5.0 g, 21.46 mmol), NH₄Cl (1.262g, 23.60 mmol) and DIPEA (11.3 ml, 64.7 mmol) in DMF (50 ml) was stirredat ˜15° C. for 15 min. Then HATU (8.16 g, 21.46 mmol) was added at 15°C., and the mixture was stirred at 15° C. for 5 h. The reaction wasquenched with water (100 mL), and the mixture was extracted with DCM(3×80 mL). The organic layer was washed with water (3×30 mL) and brine(3×30 mL), dried (Na₂SO₄). and filtered. The filtrate was concentratedin vacuo, and the resulting residue was purified by silica gelchromatography (PE:EtOAc=5:1 to 1:1) to give the title compound.

Step B. 2-(3-bromo-4-fluorophenyl)ethanamine: To a solution of2-(3-bromo-4-fluoro-phenyl)acetamide (3.0 g, 12.93 mmol) in THF (25 mL)was added dropwise BH₃.THF (24 mL, 24.00 mmol) at 0° C. The mixture wasstirred at 70° C. for 16 h. The mixture was cooled to 0° C., and water(2 mL) and conc. HCl solution (8 mL) were added to the mixture. Thereaction mixture was stirred at 70° C. for 10 min, then cooled to rt.Then the mixture was poured into NaOH aqueous solution (4 N, 25 mL). Themixture was extracted with EtOAc (3×50 mL), and the organic layer waswashed with water (5×20 mL) and brine (2×20 mL). dried over Na₂SO₄,filtered, and the filtrate was concentrated in vacuo to give crude titlecompound, which was used in the next step without further purification.

Step C. N-(3-bromo-4-fluorophenethyl)-2,2,2-trifluoroacetamide: To asolution of 2-(3-bromo-4-fluorophenyl)ethanamine (1.5 g, 6.88 mmol) andTEA (1.4 ml, 10.04 mmol) in THF (20 ml) was added TFAA (1.1 mL, 7.79mmol) at 0° C., and the mixture was stirred at 0˜19° C. for 3 h. Themixture was poured into aq. NaHCO₃(2 M, 10 mL), and the mixture wasextracted with EtOAc (3×30 mL), washed with water (2×10 mL), and brine(2×0 mL). The organic layer was dried over Na₂SO₄, and filtered, and thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatography (PE:EtOAc=20:1˜5:1) to give the title compound.

Step D.1-(6-bromo-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone.To a solution of concentrated sulfuric acid (2.5 ml. 46.9 mmol) in AcOH(10 ml) was addedN-(3-bromo-4-fluoro-phenethyl)-2,2,2-trifluoroacetamide (1.2 g, 3.82mmol) and formaldehyde (0.229 g, 7.64 mmol), and the mixture was stirredat 20° C. for 24 h. The mixture was poured into ice water (100 mL), andthe mixture was extracted with EtOAc (3×30 mL). The organic layer waswashed with water (2×20 mL) and brine (2×20 mL), dried over Na₂SO₄,filtered, and the filtrate was concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (PE:EtOAc=20:1˜5:1) togive1-(6-bromo-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanoneand1-(8-bromo-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone.

Step E. (E)-ethyl3-(7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)acrylate:To a solution of1-(8-bromo-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone(250 mg, 0.767 mmol), and1-(6-bromo-7-fluoro-3,4-dihydro-isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone(500 mg, 1.533 mmol) in dry 1,4-dioxane (10 ml) was addedtri-tert-butylphosphonium tetrafluoroborate (45 mg, 0.155 mmol), ethylacrylate (246 mg, 2.453 mmol), and N-cyclohexyl-N-methylcyclohexanamine(899 mg, 4.60 mmol). Then the mixture was degassed for 5 min with N₂,and Pd₂(dba)₃ (281 mg, 0.307 mmol) was added. The mixture was thenheated to 100° C. and stirred for 18 h in a N₂ atmosphere. EtOAc (100mL) was added, and the mixture was filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gelchromatography (PE:EtOAc=20:1 to 10:1) to afford the crude titlecompound. The mixture was purified by SFC to give title compound.

Step F: ethyl3-(7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate:To a solution of(E)-ethyl-3-(7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)acrylate(50×) mg, 1.448 mmol) in EtOH (20 mL) was added Pd—C (15 mg, 0.141mmol). The mixture was stirred at 45° C. under H₂ (30 psi) for 2 h. Themixture was filtered, washed with EtOH (10 mL), and the filtrate wasconcentrated in vacuo to give the crude title compound.

Step G. ethyl 3-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of ethyl3-(7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(200 mg, 0.576 mmol) in EtOH (10 mL) was added K₂CO₃ (239 mg, 1.728mmol). The mixture was stirred at 15° C. for 12 h, and the mixture wascooled to rt and dilated with EtOAc (20 mL). The organic layer waswashed with water (2×20 mL), dried with Na₂SO₄, and concentrated invacuo to give the crude title compound.

Intermediate 50 Ethyl2-(1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate

Step A. Tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate. Toa solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (19.17 g, 90.39mmol) in DCM (200 mL) was added TEA (18.29 g, 180.77 mmol) and Boc₂O(23.67 g, 108.46 mmol) at 0° C. After the completion of the addition,the mixture was stirred at ˜25° C. for 15 h. Water (300 mL) was added,and the mixture was extracted with EtOAc (3×100 mL). The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The resulting residuewas purified by silica gel column chromatography (PE:EtOAc=50:1 to 10:1)to give the title compound.

Step B.6-(3-ethoxy-3-oxoprop-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution of tert-butyl6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.30 g, 36.20 mmol)in dioxane (100 mL) was added ethyl acrylate (7.25 g, 72.39 mmol),(t-Bu).PHBF₄ (2.10 g, 72.40 mmol), CH₃N(C₆H₄)₂ and Pd₂(dba)₃ (3.3 g,3.62 mmol). Then the mixture was stirred at 100° C. under N₂ for 15 h.After the reaction mixture was cooled to rt, and water (200 mL) wasadded. The mixture was extracted with EtOAc (3×100 mL), and the organiclayer was washed with brine, dried (Na₂SO₄), filtered, concentrated invacuo. The resulting residue was purified by silica gel columnchromatography (PE:EtOAc=50:1 to 10:1) to give the title compound.

Step C. Tert-butyl6-(2-(ethoxycarbonyl)cyclopropyl)-3,4-dihydro-isoquino-line-2(1H)-carboxylate.To a solution of tert-butyl6-(3-ethoxy-3-oxoprop-1-en-1-yl)-3,4-dihydro-isoquinoline-2(1H)-carboxylate(6.3 g, 19.01 mmol) and Pd(OAc)₂ (0.43 g, 1.90 mmol) in DCM (200 mL) anddiethyl ether (400 mL) was added diazomethane in diethyl ether (250 mL,125 mmol) at 0° C. under a N₂ atmosphere. Then the reaction mixture wasslowly warmed to rt and stirred for 15 h. The reaction mixture wasquenched with AcOH (20 mL), washed with brine (100 mL), and the organiclayer was concentrated in vacuo. The crude product was purified bysilica gel column chromatography to give the title compound.

Step D. Ethyl2-(1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate. To asolution of tert-butyl6-(2-(ethoxycarbonyl)cyclopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.00 g, 5.79 mmol) in dioxane (5 mL) was added HCl-dioxane (4 M, 5 mL).Then the mixture was stirred at −25° C. for 2 h, and then concentratedin vacuo. The residue was purified by cation ion exchange columnchromatography (1 M NH₃-MeOH) to afford the title compound. H NMR (400MHz, CD₃OD) δ 6.90-6.97 (m, 1H), 6.81-6.90 (m, 2H), 4.14 (q, J=7.30 Hz,2H), 3.89 (s, 2H), 3.00-3.07 (m, 2H), 2.78 (t. J=5.87 Hz, 2H), 2.35-2.43(m, 1H), 1.80-1.88 (m, 1H), 1.48 (s, 1H), 1.31-1.35 (m, 1H), 1.21-1.29(m, 3H).

Intermediate 51 2-bromo-6-chloro-4-cyclobutoxybenzonitrile

Step A 2-Chloro-4-cyclobutoxy-1-nitrobenzene. To a stirred solution ofNaH (3.42 g, 85 mmol) in DMF (50 mL) was added dropwise cyclobutanol(6.16 g, 85 mmol), and the solution was stirred at 20° C. for about 5minutes. Then 2-chloro-4-fluoro-1-nitrobenzene (10.00 g, 57.0 mmol) wasadded to the reaction, and the reaction was stirred for 18 h at roomtemperature. Saturated NH₄Cl aqueous solution (100 mL) and EtOAc (100mL) were added to the reaction.

The organic layer was separated and washed with saturated NH₄Cl aqueoussolution (100 mL×4), dried over sodium sulfate and concentrated to givethe title compound.

Step B 2-Chloro-4-cyclobutoxyaniline. To a solution of2-chloro-4-cyclobutoxy-1-nitrobenzene (11.20 g, 49.2 mmol) in MeOH (100mL) was added Raney Ni (0.42 g, 4.92 mmol) at 20° C. under an argonatmosphere. Then the reaction mixture was stirred at 20° C. for 1 hunder 50 psi of H₂ atmosphere. The mixture was filtered and the filtratewas concentrated and purified on silica gel (PE/EtOAc=10:1-2:1) toafford the title compound.

Step C 2-Bromo-6-chloro-4-cyclobutoxyaniline. To a stirred solution of2-chloro-4-cyclobutoxyaniline (8.95 g, 45.3 mmol) in DCM (150 mL) wasadded bromine (2.449 mL, 47.5 mmol) by syringe at 0° C. The solution wasstirred at 0° C. for about 4 h, then aqueous saturated Na₂S₂₀₃ (20 mL)and water (100 mL) were added dropwise. The resulting mixture wasfurther stirred at room temperature for 5 min. Then the organic layerwas separated, washed with brine (100 mL×2). dried over sodium sulfateand concentrated. The resulting residue was purified by flashchromatography (PE:EA=100:1) to give the title compound.

Step D 1-Bromo-3-chloro-5-cyclobutoxy-2-iodobenzene. To a stirredsolution of 2-bromo-6-chloro-4-cyclobutoxyaniline (5.50 g, 19.89 mmol)and copper(I) iodide (5.68 g, 29.8 mmol) in acetonitrile (40 mL) at 65°C. was added dropwise isopentyl nitrite (4.66 g, 39.8 mmol). Thereaction was stirred at 65° C. for about 20 min, then cooled to roomtemperature. Then water (50 mL) and EtOAc (50 mL) were added to thereaction mixture. The organic layer was separated, washed with water (50mL×2) and brine (50 mL×2), dried over sodium sulfate and filtered. Thefiltrate was concentrated and purified by flash chromatography(petroleum ether) to afford the title compound.

Step E 2-Bromo-6-chloro-4-cyclobutoxybenzonitrile. To a stirred solutionof 1-bromo-3-chloro-5-cyclobutoxy-2-iodobenzene (4.30 g, 11.10 mmol) inDMF (25 mL) was added cyanocopper (1.988 g, 22.20 mmol). The reactionwas stirred at 110° C. overnight (18 h), then cooled to room temperatureand poured into 30 mL of saturated aqueous NH₄Cl. The resulting mixturewas stirred for about 5 min, then 30 mL of EtOAc were added, and themixture was stirred 5 min. Then the organic layer was separated, washedwith brine (60 mL×2), dried over sodium sulfate and filtered. Thefiltrate was concentrated and purified by flash chromatography(PE:EtOAc=40:1) to give partially purified crude product. The crudeproduct was further purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250*21.2 mm*4 μm) usingwater (0.2% Formic acid) and acetonitrile as eluents (Mobile phase Awater (0.2% Formic acid), Mobile phase B acetonitrile, Detectivewavelength: 220 nm) to give the title compound.

Intermediate 52 methyl3-(5-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide.6-methoxy-1,2,3,4-tetrahydro-isoquinoline (10.0 g, 61.3 mmol) wasdissolved in 48% HBr (40 mL, 354 mmol). The reaction was stirred at 100°C. for 15 h, then evaporated in vacuo to give the title compound, whichwas used directly in the next step without further purification.

Step B tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution of 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (10 g)in H₂O (100 mL) was added a solution of triethylamine (20 mL, 143 mmol)and di-tert-butyl dicarbonate (10.43 g, 47.8 mmol) in THF (30 mL)dropwise. The reaction mixture was stirred at 25° C. for 15 h. Then thereaction mixture was evaporated in vacuo to give the crude product,which was purified by silica gel (SiO₂, PE:EtOAc from 100:1 to 10:1) toafford the title compound.

Step Ctert-butyl-5-chloro-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate.Sulfuryl dichloride (3.28 g, 24.27 mmol) was added dropwise to a stirredmixture of tert-butyl6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.5 g, 22.06 mmol)in acetic acid (50 mL) at room temperature (−25° C.), and the mixturewas stirred at room temperature (˜25° C.) for 1.5 h. Then the mixturewas concentrated. The resulting residue was dissolved in anhydrous DMF(50.0 mL), and Et₃N (9.22 mL, 66.2 mmol) and BOC-Anhydride (6.15 mL,26.5 mmol) were added. Then the mixture was stirred at room temperature(25° C.) for 3 h, then concentrated in vacuo. Water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with aqueous ammonium chloride(30 mL), dried over Na₂SO₄, and filtered. The filtrate was evaporatedunder reduced pressure to give a residue, which was purified by columnchromatography on silica gel (SiO₂), eluting with EA/PE=1:20-1:5 to givethe title compound.

Step Dtert-butyl-5-chloro-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a stirred solution of tert-butyl5-chloro-6-hydroxy-3,4-dihydroisoquinoline-2(1H) carboxylate (1.4 g,4.93 mmol) in CH₂Cl₂ (20 mL) was added pyridine (1.171 g, 14.8 mmol) andtrifluoromethanesulfonic anhydride (2.09 g, 7.40 mmol) dropwise at 0° C.The reaction mixture was warmed to room temperature (20° C.) and stirredfor 30 min. Then the solvent was removed by rotary evaporation, and theresulting mixture was diluted with water (20 mL) and extracted with DCM(20 mL×3). The combined organic layers were evaporated, and theresulting crude product was purified on silica gel (SiO₂,PE/EtOAc=20:1-10:1) to give the title compound.

Step Etert-butyl-6-(3-(tert-butoxy)-3-oxopropyl)-5-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution of tert-butyl5-chloro-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(0.92 g, 2.1 mmol) in toluene (20 ml) and H₂O (2 ml) was added potassium3-trifluoroboratopropionate tert-butyl ester (0.49 g, 2.1 mmol) andsodium carbonate (0.66 g, 6.3 mmol), followed by the addition ofG2Ruphos (75 mg, 0.1 mmol) under a N₂ atmosphere. The reaction mixturewas stirred at 90° C. for 12 h, then poured into water (10 mL) andextracted with EA (30 mL×3). The combined organic layers were washedwith water (10 mL×3), and dried over Na₂SO₄. After filtration andconcentration, the resulting residue was purified by prep-HPLC (acid) togive the title compound.

Step F methyl 3-(5-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of tert-butyl6-(3-(tert-butoxy)-3-oxopropyl)-5-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate(395 mg, 1 mmol) in MeOH (10 mL) was added HCl-MeOH (5 mL, 3M). Themixture was stirred at 70° C. for 4 h. then the reaction mixture wascooled to room temperature and concentrated to give the title compound.MS (ESI) m/z: 254 [M+H+]

Intermediate 53 1-bromo-2,3-dichloro-5-(trifluoromethoxy)benzene

1-bromo-2,3-dichloro-5-(trifluoromethoxy)benzene. A suspension ofcopper(II) chloride (403 mg, 3.00 mmol) and tert-butyl nitrite (309 mg,3.00 mmol) in anhydrous MeCN (15 mL) was warmed to 65° C. Then asolution of 2-bromo-6-chloro-4-(trifluoromethoxy)aniline (870 mg, 3.00mmol) in anhydrous MeCN (5 mL) was added dropwise. The reaction mixturewas stirred for 1 h at 65° C., then allowed to cool to 25° C. and pouredinto 1 M HCl (15 mL). The acidic mixture was neutralized with saturatedNaHCO₃ and aqueous ammonia (35%, 5 mL). The mixture was extracted withDCM (25 mL) and then washed with aqueous ammonia (17.5%, 20 mL) andbrine (2×20 mL). The resulting crude product was purified by column(SiO₂. eluting with PE) to give the title compound.

Intermediate 54 methyl3-(5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate

Step A tert-butyl5-methyl-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2(1H)-carboxylate. Toa solution of N-Boc-4-piperidone (19.8 g, 9.92 mol) in toluene (400 ml)was added pyrrolidine (10.9 g, 1.55 equiv). The reaction was heated toreflux for 2 h and the water was removed by azeotropic distillation. Thereaction was then concentrated in vacuo and cooled to 20° C. Toluene(100 mL) was added to the residue, followed by a slurry of hydroquinone(64 mg, 0.5 mol %) in toluene (3 mL). The reaction was cooled to 10° C.,and ethyl vinyl ketone (8.30 g, 0.99 eq) was added. The solution washeated to 40° C. for 1 h and then heated to 105° C. for 18 h, beforebeing cooled to 26-28° C. The organic layer was washed with saturatedNH₄Cl solution, followed by water (100 mL). The organic phase wasconcentrated to give a toluene solution, which was used directly in thenext reaction.

Step B tert-butyl5-methyl-6-((triethylsilyl)oxy)-3,4,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate.To a solution of tert-butyl5-methyl-6-oxo-3,4,6,7,8,8a-hexahydro-isoquinoline-2 (1H)-carboxylate(700 mg, 2.64 mmol) in THF (10 mL) was added LiHMDS (2 mL, 4 mmol) at 0°C. for 0.2 h. The reaction mixture was stirred at 0° C. for 5 h, thenpoured into ice water (30 mL) and extracted with EA (40 mL). The organiclayer was washed with brine (20 mL). and dried over Na₂SO₄. Afterfiltration, the solvent was concentrated to afford the title compound,which used in the next step without further purification

Step C tert-butyl6-hydroxy-5-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. To asolution of tert-butyl5-methyl-6-((triethylsilyl)oxy)-3,4,8,8a-tetrahydroisoquinoline-2-(1H)-carboxylate(750 mg, 1.581 mmol) in THF (10 mL) was added Pd(OAc)₂ (426 mg, 1.897mmol) at 10° C. The reaction mixture was stirred at 20° C. for 10 h,Then potassium formate (199 mg, 2.371 mmol) in water (0.5 mL) was added,and the mixture was stirred at 20° C. for 2 h. TBAF (0.790 ml, 0.790mmol) was added to the reaction and the reaction was stirred at 20° C.for 2 h, then poured into ice water (30 mL) and extracted with EA (40mL*2). The combined organic layers were washed with brine (20 mL) anddried over anhydrous Na₂SO₄. After filtration and concentration, theresulting residue was purified by flash chromatography (SiO₂), elutingwith 0-20% EA in PE to give the title compound.

Step D tert-butyl5-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution oftert-butyl-6-hydroxy-5-methyl-3,4-dihydro-isoquinoline-2(1H)-carboxylate(230 mg, 0.873 mmol), pyridine (0.21 mL, 2.6 mmol) in DCM (5 mL) wasadded Tf₂O (0.18 mL, 1 mmol) at −35° C. for 0.2 h. The mixture wasstirred at −35° C. for 1 h, then poured into ice HCl (0.5N, 10 mL) andextracted with EA (20 mL*2). The combined organic layers were washedwith NaHCO₃ (10 mL) and brine (20 mL). After filtration, the filtratewas concentrated to give the title compound, which was used in the nextstep without further purification.

Step Etert-butyl-6-(3-(tert-butoxy)-3-oxopropyl)-5-methyl-3,4-dihydroisoquinoline-2(H)-carboxylate.To a solution of tert-butyl5-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.8 g, 4.55 mmol), potassium 3-trifluoroborato-propionate tert-butylester (3.22 g, 13.66 mmol), Na₂CO₃ (1.45 g, 13.66 mmol) in water (2 mL)and toluene (20 mL) was added G2-Ru-Phos (0.354 g, 0.455 mmol). Themixture was stirred at 100° C. for 10 h, then the solvent was removedunder reduced pressure. The resulting mixture was purified by prep-HPLC(TFA) to afford the title compound.

Step F methyl 3-(5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.The mixture of tert-butyl6-(3-(tert-butoxy)-3-oxopropyl)-5-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.2 g, 3.2 mmol) in HCl-MeOH (4M, 15 mL, 60 mmol) was stirred at 65° C.for 10 h, then the solvent was removed under reduced pressure to givethe title compound, which was used in the next step without furtherpurification. MS (ESI) m/z: 254.1 [M+H+]

Example 13-(2-(2-chloro-5-cyclobutoxy-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid

Step A.Methyl-3-(2-(2-chloro-5-cyclobutoxy-4-methoxyphenyl)-1,2,3,4-tetra-hydro-isoquinolin-6-yl)propanoate:Methyl-3-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-propanoate (100 mg, 0.456mmol). 1-bromo-2-chloro-5-cyclo-butoxy-4-methoxybenzene (Intermediate20, 146 mg, 0.502 mmol), Cs₂CO₃ (297 mg, 0.912 mmol), Xantphos (53 mg,0.092 mmol) and Pd₂(dba)₃ (42 mg, 0.046 mmol) in 1,4-dioxane (5 mL) werestirred at 90° C. for 18 h under a N₂ atmosphere. The mixture wasdiluted with water (15 mL). extracted with EtOAc (3×20 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified via silica gel PTLC (PE:EtOAc=5:1) to afford thetitle compound. m/z 430.1 [M+1]⁺.

Step-B.3-(2-(2-chloro-5-cyclobutoxy-4-methoxyphenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid: To a solution of methyl3-(2-(2-chloro-5-cyclobutoxy-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(60 mg, 0.140 mmol) in THF (4 mL) and water (2 mL), was added LiOHhydrate (12 mg, 0.286 mmol). Then the mixture was stirred at 17° C. for2 h. After acidification to pH 2-3, the solvent was removed in vacuo.The residue was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 column (250×21.2 mm×4μm) using water (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A:water (0.2% Formic acid), Mobile phase B: CH₃CN. Detector wavelength:220 nm) followed by concentration (below 50° C.) in vacuo to give thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 6.98-7.08 (m, 3H), 6.91 (s,1H), 6.56 (s, 1H), 4.55 (q, J=7.14 Hz, 1H), 4.18 (s, 2H), 3.94 (s, 3H),3.33 (t, J=7.48 Hz, 2H), 2.90-2.99 m, 4H), 2.68 (t, J=7.63 Hz, 2H),2.28-2.38 (m, 2H), 2.18-2.26 (m, 2H), 1.82-1.84 (m, 1H), 1.60-1.68 (m,1H); m/z=416.1 [M+1]⁺.

Example 23-(2-(3-(difluoromethyl)-2-fluoro-5-(pyridin-2-yloxy)phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid

Step A. Methyl3-(2-(3-(difluoromethyl)-2-fluoro-5-(pyridin-2-yloxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate:To a stirred solution of methyl3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (100 mg, 0.456 mmol) in1,4-dioxane (3 mL) was added2-(3-bromo-5-(difluoromethyl)-4-fluorophenoxy)pyridine (Intermediate 21,160 mg, 0.502 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (39 mg, 0.092mmol) and Cs₂CO₃ (223 mg, 0.684 mmol). The mixture was degassed with N₂,and Pd₂(dba)₃ (42 mg, 0.046 mmol) was added. The mixture was heated to100° C. and stirred for 18 h. The reaction mixture was diluted withEtOAc (5 mL) and filtered. The filtrate was concentrated in vacuo toafford the crude title compound, which was used in the next step withoutfurther purification.

Step B.3-(2-(3-(difluoromethyl)-2-fluoro-5-(pyridin-2-yloxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid: To a stirred solution of methyl3-(2-(3-(difluoromethyl)-2-fluoro-5-(pyridin-2-yloxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (80 mg, crude) in THF (5 ml) was added LiOH H₂O (40 mg, 0.953mmol) and water (2.5 mL). The mixture was stirred for 5 h at rt, and HCl(3N) was added to adjust the mixture to pH=2-3. Then the mixture wasdiluted with EtOAc (20 mL). The organic layer was separated, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CN aseluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN. Detector wavelength: 220 nm) followed by concentration (below 50°C.) in vacuo to afford the title compound. ¹H-NMR (400 MHz, CDCl₃) δ8.19 (d, J=7.6 Hz, 1H), 7.72 (t, J=6.8 Hz, 1H), 7.02-6.91 (m, 4H),6.89-6.76 (m, H). 4.28 (m, 2H), 3.46 (t, J=5.6 Hz, 2H), 2.97-2.90 (m,2H), 2.69-2.65 (m, 2H): min=443.0 [M+1]⁺.

Example 33-(2-(2,3-difluoro-5-(3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid (trans)

Step A. Ethyl3-(2-(2,3-difluoro-5-(3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(trans): To a solution of ethyl3-(1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoate (84 mg, 0.359 mmol) in1,4-dioxane (5 mL) was added 2,3-difluoro-5-(3-methoxycyclobutoxy)phenyltrifluoromethanesulfonate (Intermediate 4, 130 mg, 0.359 mmol), Cs₂CO₃(351 mg, 1.077 mmol), XPhos (35 mg, 0.073 mmol) and Pd₂(dba)₃ (33 mg,0.036 mmol). The mixture was stirred at 90° C. for 15 h under a N₂atmosphere. The reaction mixture was concentrated in vacuo, and theresidue was diluted with water (20 mL) and extracted with EtOAc (3×30mL). The organic layer was dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography(PE:EtOAc=20:1 to 5:1) to afford the title compound. m/Z 446.2 [M+1]⁺.

Step-B-3-(2-(2,3-difluoro-5-(3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid (trans): To a solution of ethyl3-(2-(2,3-difluoro-5-(3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(20 mg, 0.045 mmol) in THF (2 mL), MeOH (2 mL) and Water (1 mL) wasadded LiOH hydrate (4 mg, 0.095 mmol). The mixture was stirred at rt for2 h. After acidification with 1N HCl to pH=2, the solvent was removed invacuo. The residue was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid). Mobile phase B: CH₃CN. Detector wavelength: 220 nm)followed by concentration (below 50° C.) in vacuo to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 7.05 (s, 2H), 7.00 (s, 1H),6.12-6.22 (m, 2H), 4.63-4.70 (m, 1H), 4.29 (s, 2H), 4.08-4.14 (m, 1H),3.48 (t, J=5.67 Hz, 2H). 3.28 (s, 3H), 2.87-2.97 (m, 4H), 2.64-2.72 (m,2H), 2.32-2.39 (m, 4H): m/z=418.1 [M+1]⁺.

Example 43-(2-(2-fluoro-4-methoxy-5-((5-methylthiazol-2-yl)oxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid

Step A. Methyl3-(2-(2-fluoro-4-methoxy-5-((5-methylthiazol-2-yl)oxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate:To a solution of methyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(100 mg, 0.456 mmol) in dioxane (4.00 mL) was added2-(5-bromo-4-fluoro-2-methoxyphenoxy)-5-methylthiazole (Intermediate 10,214 mg, 0.673 mmol), Cs₂CO₃ (446 mg, 1.368 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (40 mg, 0.094mmol) and Pd₂(dba)₃ (42 mg, 0.046 mmol). Then the reaction mixture wasplaced under nitrogen and stirred at 100° C. for 24 h. The mixture wasconcentrated in vacuo, and water (30 mL) was added to the residue. Themixture was extracted with EtOAc (30 mL×2). and the organic layer wasconcentrated in vacuo. The resulting crude product was purified bysilica gel PTLC (PE/EtOAc=5:1) to give the title compound.

Step B.3-(2-(2-fluoro-4-methoxy-5-((5-methylthiazol-2-yl)oxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid: To a solution of methyl3-(2-(2-fluoro-4-methoxy-5-((5-methylthiazol-2-yl)oxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (30 mg, 0.066 mmol) in THF (1 mL), MeOH (1 mL) and water (0.5mL) was added LiOH hydrate (14 mg, 0.334 mmol). Then the reactionmixture was stirred at rt for 2 h. The mixture was acidified with HCl(0.25 mL, 6 N) and concentrated in vacuo. The crude product as purifiedby reverse phase HPLC on a GILSON 281 instrument fitted with aPhenomenex Synergi C18 (250×21.2 mm×4 μm) using water (0.2% Formic acid)and CH₃CN as eluents (Mobile phase A: water (0.2% Formic acid). Mobilephase B: CH₃CN, Detector wavelength: 220 nm) followed by concentrationin vacuo to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ 6.94-7.04(m, 4H), 6.78-6.86 (m, 2H), 4.19 (s, 2H) 3.79 (s, 3H), 3.35 (t, J=5.48Hz, 2H), 2.88-3.00 (m, 4H), 2.62-2.70 (m, 2H), 2.33 (s, 3H): m/z=443.1[M+1]⁺

Example 53-(2-(6-cyclobutoxy-3-fluoropyridin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)-propanoicacid

Step A. (methyl3-(2-(6-cyclobutoxy-3-fluoropyridin-2-yl)-1,2,3,4-tetrahydroiso-quinolin-6-yl)propanoate:To a solution of 2-bromo-6-cyclobutoxy-3-fluoropyridine (Intermediate 2,150 mg, 0.61 mmol) and ethyl3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (Intermediate 7, 142mg, 0.61 mmol) in 1,4-dioxane (10 ml) was added Cs₂CO₃ (397 mg, 1.22mmol) and XPhos precatalyst (45.0 mg, 0.06 mmol), and the mixture wasstirred at 90° C. for 18 h under a N₂ atmosphere. The mixture wasdiluted with water (10 mL) and extracted with EtOAc (10 mL). The organiclayer was collected, washed with brine (10 mL), dried over anhydrousNa₂SO₄. filtered, and concentrated under in vacuo. The residue waspurified by silica gel column chromatography (PE:EtOAc from 10:1 to 1:1)to afford the title compound.

Step B.3-(2-(6-cyclobutoxy-3-fluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid: A mixture of ethyl3-(2-(6-cyclobutoxy-3-fluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(80 mg, 0.20 mmol) and LiOH hydrate (20 mg, 0.47 mmol) in THF (4 mL) andwater (2 mL) was stirred at rt for 1 h. The mixture was acidified with 1N HCl (10 mL) to pH=˜6, and extracted with EtOAc (20 mL). The organiclayer was separated, washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The crude product wasfurther purified by reverse phase HPLC on a GILSON 281 instrument fittedwith a Phenomenex Synergi C18 (250×21.2 mm×4 μm) using water (0.2%Formic acid) and CH₃CN as eluents (Mobile phase A: water (0.2% Formicacid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm), followed byconcentration (below 50° C.) in vacuo to afford the title compound. ¹HNMR (400 MHz, CD₃OD) δ 7.16 (d, J=3.6 Hz, 1H), 7.13 (s, 1H), 7.08 (d,J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.01 (dd, J=1.6, 8.4 Hz, 1H),5.02-4.95 (m, 1H), 4.61 (s, 2H), 3.78 (t, J=6.0 hZ, 2H), 2.96-2.92 (m,4H), 2.69-2.66 (m, 2H), 2.42-2.40 (m, 2H), 2.18-2.14 (m, 2H), 1.82-1.81(m, 1H), 1.70-1.69 (m, 1H): min=371.0 [M+1]⁺.

Example 63-(2-(5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid

Step A. methyl3-(2-(5-cyclobutoxy-2-fluoro-4-nitrophenyl)-1-methyl-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoate:To a solution of methyl3-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoate (Intermediate45, 250 mg, 1.07 mmol) was added1-cyclobutoxy-4,5-difluoro-2-nitrobenzene (Intermediate 3 Step B, 319mg, 1.39 mmol) and Cs₂CO₃ (698 mg, 2.14 mmol). The mixture was heated at150° C. and stirred for 3 h. Then the reaction mixture was cooled to rtand EtOAc (20 mL) was added. The mixture was washed with brine, driedover Na₂SO₄ and evaporated in vacuo. The residue was purified by silicagel PTLC (PE:EtOAc=4:1) to afford the title compound.

Step B. Methyl3-(2-(4-amino-5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroiso-quinolin-6-yl)propanoate:To a solution of methyl3-(2-(5-cyclobutoxy-2-fluoro-4-nitrophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(180 mg, 0.41 mmol) in MeOH (10 ml) was added Fe powder (114 mg, 2.03mmol), NH₄Cl (109 mg, 2.03 mmol) and water (1 mL). The mixture washeated to reflux and stirred overnight. The mixture was filtered, andthe filtrate was concentrated in vacuo to afford the title compound,which was taken to next step without further purification.

Step C. methyl3-(2-(5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroiso-quinolin-6-yl)propanoate:To a solution of methyl3-(2-(4-amino-5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(150 mg, 0.36 mmol) in dry THF (5 ml) was added isopentyl nitrite (128mg, 1.09 mmol). The mixture was heated to reflux for 3 h. The reactionmixture was concentrated in vacuo to give the crude title compound,which was taken to next step without further purification.

Step D.3-(2-(5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquino-lin-6-yl)propanoicacid: To a solution of methyl3-(2-(5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(150 mg, 0.38 mmol) in THF (3 ml) was added LiOH.H₂O (38 mg, 0.91 mmol)and water (1.5 ml). The final mixture was stirred overnight at rt. ThenHCl (3 N aqueous solution) was added to adjust the pH to 2-3. Theorganic layer was separated, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm.)to afford the title compound. m/z 384.1 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃)δ: 7.06 (m, 2H), 6.96 (s, 1H), 6.89 (m, 1H), 4.75 (m, 1H), 4.52 (m, 1H),3.47 (m, 1H), 2.92-3.12 (m, 3H), 2.66-2.75 (m, 3H), 2.33 (m, 2H),2.17-2.25 (m, 2H), 1.84 (m, 1H), 1.81 (m, 1H), 1.34 (d, J=6.8 Hz, 3H).

Example 73-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)butanoicacid

Step A. ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)butanoatehydrochloride (slow eluting): To a solution of tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(92 mg, 0.265 mmol) in MeOH (3 ml) was added 4 M HCl (1 mL, 4.0 mmol)and stirred 15° C. for 1 h. The mixture was concentrated in vacuo, togive the crude product which was used directly in the next step withoutfurther purification. m/z 247.1 [M+H]⁺.

Step B. ethyl3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-Butanoate:To a solution of ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)butanoatehydrochloride from the previous step (65 mg, 0.255 mmol) and2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (66 mg, 0.255 mmol) indioxane (3 mL) was added XANTPHOS (25 mg, 0.043 mmol) and Pd₂(dba)₃ (49mg, 0.054 mmol), followed by the addition of Cs₂CO₃ (138 mg, 0.423mmol). The reaction mixture was stirred at 100° C. under a N₂ atmospherefor 12 h. The reaction mixture was partitioned between EtOAc (50 mL) andwater (50 mL), and the organic layer was washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The crude titlecompound was used in the next step without further purification. m/z426.1 [M+H]⁺.

Step C.3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)butanoicacid: To a solution of ethyl3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)butanoate(20 mg, 0.047 mmol) in THF-MeOH—H₂O (2:2:1 2.5 mL) was added LiOHhydrate (2 mg, 0.048 mmol) at 25° C. The reaction mixture was stirred at25° C. for 2 h. The reaction mixture was concentrated in vacuo. and theresidue was acidified with diluted 1 M HCl until pH<5. The reactionmixture was partitioned between EtOAc (20 mL) and water (20 mL), and theseparated organic layer was washed with brine (20 mL). The organic layerwas concentrated in vacuo. The crude product was purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CN aseluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN, Detector wavelength: 220 nm), followed by concentration (below50° C.) in vacuo to give the title compound. ¹HNMR (400 MHz, CDCl₃)δ:7.00-7.09 (m, 4H) 6.83 (d, J=6.65 Hz, 1H) 6.77 (d, J=8.22 Hz, 1H) 4.28(s, 2H) 3.46 (t, J=5.67 Hz, 2H) 3.21-3.30 (m, 1H) 3.00 (t, J=5.48 Hz,2H) 2.56-2.72 (m, 2H) 1.32 (d, J=6.65 Hz, 3H). MS m/z 397.1 [M+H]⁺.

Example 83-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)-butanoicacid

Step A-ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)butanoatehydrochloride (slow eluting): To a solution of tert-butyl6-(4-ethoxy-4-oxobutan-2-yl)-3,4-dihydro isoquinoline-2(1H)-carboxylate(92 mg, 0.265 mmol, slower eluting) in MeOH (3 mL) was added 4M HCl (1mL, 4.00 mmol) and stirred 15° C. for 1 h. The mixture was evaporated invacuo, to give the crude title compound which was used in the next stepwithout further purification. m/z 247.1 [M+H]⁺.

Step B.Ethyl-3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydro-isoquino-lin-6-yl)butanoate:To a solution of ethyl 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)butanoatehydrochloride (65 mg, 0.229 mmol) and2-bromo-1-fluoro-4-(trifluoro-methoxy)benzene (71 mg, 0.274 mmol) indioxane (3 ml) was added XANTPHOS (3 mg, 0.005 mmol), Pd₂(dba)₃ (49 mg,0.054 mmol) and Cs₂CO₃ (149 mg, 0.458 mmol). The mixture stirred at 100°C. under N₂ atmosphere for 12 h. The reaction mixture was partitionedbetween EtOAc (50 mL) and water (50 mL). and the organic layer waswashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The crude title compound was used in the next step withoutfurther purification. nm/z 426.1 [M+H]⁺.

Step C.3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)butanoicacid (peak 2): To a solution of crude ethyl3-(2-(2-fluoro-5-(trifluoromethoxy)-phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)butanoate(20 mg, 0.047 mmol) in THF-MeOH—H₂O (2:2:1, 2.5 mL) was added LiOHhydrate (2 mg, 0.048 mmol) at 25° C., and the mixture was stirred at 25°C. for 2 h. The mixture was concentrated in vacuo. and the resultingresidue was acidified with diluted 1 M HCl until pH<5. The reactionmixture was partitioned between EtOAc (20 mL) and water (20 mL), and theorganic layer was washed with brine (20 mL). The organic layer wasconcentrated in vacuo, and the crude product was purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CN aseluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN, Detector wavelength: 220 nm) followed by concentration (below 50°C.) in vacuo to obtain the title compound. ¹HNMR (400 MHz, ppm) S: 7.06(s, 2H) 7.00-7.05 (m, 2H) 6.83 (d, J=7.04 Hz, 1H) 6.77 (d, J=8.61 Hz,1H) 4.27 (s, 2H) 3.45 (t, J=5.67 Hz, 2H) 3.25 (br. s., 1H) 2.99 (t,J=5.28 Hz, 2H) 2.67 (br s., 2H) 1.32 (d, J=5.87 Hz, 3H); m/z 397.1[M+H]⁺.

The examples in Table 1 were prepared from the appropriate startingmaterials described previously or commercially available startingmaterials available using procedures described in Examples 1-8.

TABLE 1 Example Structure Name [M + H]+ 9

3-(2-{3-chloro-2-fluoro- 5-[(5-methyl-1,3- thiazol-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 447.0 10

3-{2-[5-(cyclobutyloxy)- 3-(difluoromethyl)-2- fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 420.1 11

3-{2-[5-(cyclobutyloxy)- 2,3-difluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 388.1 12

3-{2-[3-cyano- 5-(cyclobutyloxy)-2- fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 395.1 13

3-{2-[2-fluoro- 3-methoxy- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 413.1 14

3-(2-{3-(difluoromethyl)- 2-fluoro-5-[(5-methyl- 1,3-thiazol-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 463.1 15

3-{2-[3-chloro-2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 418.0 16

3-(2-{3-(difluoromethyl)- 2-fluoro-5-[(5- methylpyridin-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 457.1 17

3-(2-{2-fluoro-3- methoxy-5-[(5-methyl- 1,3-thiazol-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 443.2 18

3-{2-[5-(cyclobutyloxy)- 2-fluoro-3- methoxyphenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 400.1 19

3-{2-[5-(cyclobutyloxy)- 2-fluorophenyl]-1,2,3,4-tetrahydroiso-quinolin- 6-yl}propanoic acid 370.1 20

3-(2-{2,3-difluoro- 5-[(trans-3- methoxycyclobutyl) oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin- 6-yl)propanoic acid 418.1 21

3-(2-{2-fluoro-4-methoxy- 5-[(5-methyl-1,3- thiazol-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 443.1 22

3-{2-[4-chloro-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 410.1 23

3-{2-[5- (cyclobutylmethyl)- 2-fluorophenyl]-5-fluoro- 1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 386.2 24

3-{2-[2-chloro- 5-(cyclobutyloxy)- 4-methoxyphenyl]- 1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 416.1 25

3-{2-[6-(cyclobutyloxy)- 3-fluoropyridin-2-yl]- 1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 371.0 26

3-{2-[2-(cyclobutylsulfanyl)- 5-fluoropyridin- 4-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 387.1 27

3-{2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 384.3 28

3-(2-{2-fluoro-4- methoxy-5-[(5- methylpyridin-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 437.1 29

3-{2-[6-fluoro- 3-(trifluoromethyl)- 1,2-benzisoxazol- 5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 409.0 30

3-{7-fluoro-2-[2- fluoro-5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 402.1 31

3-{2-[5-(cyclobutyloxy)- 2-fluoro-4-methoxyphenyl]- 1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 400.1 32

3-{2-[5-(cyclobutyloxy)- 2,3-difluorophenyl]-1- methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 402.1 33

3-{2-[2-fluoro- 5-(pyrazin-2-yloxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 394.1 34

3-(2-{3-cyano-2- fluoro-5-[(trans-3- methoxycyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 425.4 35

3-(2-{3-(difluoromethyl)- 2-fluoro-5-[(5-fluoropyridin-2-yl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid461.1 36

3-{2-[5-(cyclobutyloxy)- 2-fluorophenyl]-1- methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 384.2 37

3-{2-[2-chloro- 5-(cyclobutyloxy)-3- fluorophenyl]-1- methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 418.1 38

3-{2-[6-(cyclobutylsulfanyl) pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 369.1 39

3-{2-[5-(cyclobutyloxy)- 2-fluorophenyl]-1- methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 384.1 40

3-{2-[3,5-dichloro- 4-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 41

3-{2-[6-(cyclobutyloxy) pyrazin-2-yl]-1,2,3,4- tetrahydroisoquinolin-6-yl}propanoic acid 354.1 42

3-{2-[2-cyano- 5-(cyclobutyloxy)-4- methoxyphenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 407.2 43

3-{2-[4-cyano-1-(4- methoxyphenyl)-3-methyl- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 417.3 44

3-{2-[2-cyano-3-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 409.1 45

3-{2-[2-chloro- 5-(cyclobutyloxy)- 3-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 404.1 46

3-{2-[2-cyano- 5-(cyclobutyloxy) phenyl]-1,2,3,4- tetrahydroisoquinolin-6-yl}propanoic acid 395.1 47

3-{2-[4-fluoro-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 394.2 48

3-(2-{2-cyano-5-[(trans- 3-methoxycyclobutyl) oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin- 6-yl)-propanoic acid 407.2 49

3-{2-[5-(cyclobutyloxy)- 2,3-difluorophenyl]- 1-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 402.1 50

3-(2-{[3-(4-chlorophenyl)- 5-(trifluoromethyl) isothiazol-4-yl]methyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 481.1 51

3-{8-fluoro-2-[2- fluoro-5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 402.1 52

3-{2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}-2-methyl- propanoic acid 398.1 53

3-{2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}butanoic acid 398.1 54

3-{2-[3-chloro- 5-(cyclobutyloxy)-2- fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 404.1 55

3-{2-[2-cyano- 5-(cyclobutyloxy)- 3-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 395.0

Example 563-(2-(5-(cyclobutyldifluoromethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid

Step A.Ethyl-3-(2-(5-(cyclobutyldifluoromethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (Intermediate42, 100 mg, 0.398 mmol) in 1,4-dioxane (5 mL), were added2-bromo-4-(cyclobutyldifluoromethyl)-1-fluorobenzene (111 mg, 0.398mmol), Cs₂CO₃ (389 mg, 1.194 mmol) and X-Phos precatalyst (30 mg, 0.041mmol), then the mixture was stirred at 90° C. for 18 h under N₂. Aftercompletion of the reaction according to TLC (PE:EtOAc=10:1), the solventwas removed under reduced pressure. The residue was diluted with water(20 mL), and extracted with EtOAc (2×30 mL). The organic layer was driedover Na₂SO₄, filtrated and concentrated. The residue was purified bysilica gel chromatography (PE:EtOAc=30:1) to afford the title compound.m/z=450.2 [M+1]⁺.

Step-B.3-(2-(5-(cyclobutyldifluoromethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid. To a solution of ethyl3-(2-(5-(cyclobutyl-difluoromethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(60 mg, 0.133 mmol) in THF (2 mL), MeOH (2 mL) and water (1 mL), wasadded LiOH hydrate (12 mg, 0.286 mmol), then the mixture was stirred atr.t. (ca. 27° C.) for 2 h. After acidification with 1N HCl to pH=0.02,the solvent was removed under reduced pressure. The residue was purifiedby reverse phase HPLC on a GILSON 281 instrument fitted with aPhenomenex Synergi C18 (250×21.2 mm×4 μm) using water (0.2% Formic acid)and CH₃CN as eluents (Mobile phase A: water (0.2% Formic acid), Mobilephase B: CH₃CN, Detector wavelength: 220 nm) followed by concentration(below 50° C.) to obtain the title compound. ¹H NMR (400 MHz, CDCl₃)δ6.98-7.12 (m, 4H), 6.86 (d, J=7.83 Hz, 1H), 4.27 (s, 2H), 3.44 (t,J=5.87 Hz, 2H), 2.87-3.03 (m, 5H), 2.69 (t, J=7.63 Hz, 2H), 2.15-2.25(m, 2H), 1.85-1.99 (m, 4H); m/z=422.1 [M+1]⁺.

Example 573-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2-methylpropanoicacid

Step A. ethyl3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoate:To a solution of ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl propanoate(Intermediate 47, 300 mg, 1.131 mmol) in THF (10 mL) were added1-bromo-3-chloro-2-fluoro-5-(trifluoromethoxy)-benzene (Intermediate 5,398 mg, 1.357 mmol), sodium 2-methylpropan-2-olate (1.1 mL, 2.200 mmol,2 M, THF solution) and t-Buxphos-precatalyst (116 mg, 0.170 mmol)) atrt. Then the reaction mixture was placed under nitrogen atmosphere andstirred at 40° C. for 15 h. The mixture was diluted with water (25 mL),extracted with EtOAc (40 mL×2). and the organic layer was evaporated.The crude product was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm)followed by concentration (below 50° C.) to obtain the title compound.

Step B. tert-butyl ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methyl-propanoate: Toa solution of ethyl3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)-phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoate(300 mg, 0.565 mmol) in THF (6 mL) and water (3 mL) was added LiOHhydrate (119 mg, 2.83 mmol). The reaction mixture was stirred at rt for4 h. The mixture was acidified to pH˜2 with HCl (2 mL, 1 N), extractedwith EtOAc (20 mL×2), and the organic layer was evaporated to give thetitle compound, which was used directly in next step without furtherpurification.

Step C.3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2-methylpropanoylchloride. To a solution of3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoicacid (250 mg, 0.365 mmol) in DCM (10 mL) was added SOCl₂ (0.5 ml, 6.85mmol) with stirring at −78° C. The mixture was placed under a N₂atmosphere and stirred at rt overnight (˜18 h). The reaction mixture wasconcentrated in vacuo to give the title compound, which was directlyused in the next step without further purification.

Step D.(4R)-4-benzyl-3-(3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoyl)oxazolidin-2-one.To a solution of (R)-4-benzyloxazolidin-2-one (91 mg, 0.513 mmol) in THF(10 mL) was added NaH (28 mg, 0.700 mmol) (60% in NaH) with stirring at0° C. The mixture was placed under N₂ atmosphere and stirred at rt forabout 30 min. Then a solution of3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2-methylpropanoylchloride (160 mg, 0.342 mmol) in THF (2 mL) was added dropwise at rt.The mixture was stirred at rt for about 2 h. The reaction mixture wasdiluted with water (10 mL) and EtOAc (15 mL), and was stirred for about10 min at rt (15° C.). Then the organic layer was separated and washedwith water (2×10 m), brine (2×10 m), dried (Na₂SO₄) and filtered. Thefiltrate was concentrated to give crude product, which was purified byreverse phase HPLC on a GILSON 281 instrument fitted with a PhenomenexSynergi C18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CNas eluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN, Detector wavelength: 220 nm) followed by concentration (below 50°C.) to obtain the title compound.

Step E.(4R)-4-benzyl-3-(3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoyl)oxazolidin-2-one.(4R)-4-benzyl-3-(3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoyl)oxazolidin-2-one(90 mg, 0.145 mmol) was separated by SFC-HPLC on Chiralpak AD-3 150×4.6mm I.D., 3 um Mobile phase: A:CO₂ B:methanol (0.05% DEA) Gradient: from5% to 40% of B in 5.0 min and hold 40% for 2.5 min, then 5% of B for 2.5min Flow rate: 2.5 mL/min Column temperature: 35° C. Wavelength: 220 nmto give(4R)-4-benzyl-3-(3-(2-(3-chloro-2-fluoro-5-(trifluoro-methoxy)phenyl)5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)-2-methylpropanoyl)oxazolidin-2-oneand(4R)-4-benzyl-3-(3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpropanoyl)oxazolidin-2-one.

Step F.3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)-2-methylpropanoicacid. To a solution of(4R)-4-benzyl-3-(3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl)-2-methylpropanoyl)oxazolidin-2-one(30 mg, 0.046 mmol) in THF (4 mL) and water (2 ml) at 0° C. was addeddropwise a solution of lithium peroxide prepared by adding H₂O₂ (0.065ml, 0.741 mmol) to LiOH hydrate (6 mg, 0.143 mmol) in water (0.2 mL).The reaction mixture was stirred for 0° C. for 1 h and then quenchedwith saturated aqueous Na₂SO₃ (0.5 mL). The mixture was diluted withwater (10 mL) and acidified with 1 N HCl to pH=2, and extracted withEtOAc (2×10 mL). The EtOAc extracts were combined, washed with brine (5mL), dried over anhydrous MgSO₄, and concentrated. The residue waspurified by reverse phase HPLC on a GILSON 281 instrument fitted with aPhenomenex Synergi C18 (250×21.2 mm×4 rpm) using water (0.2% Formicacid) and CH₃CN as eluents (Mobile phase A: water (0.2% Formic acid),Mobile phase B: CH₃CN, Detector wavelength: 220 nm), followed byconcentration (below 50° C.) to obtain the title compound. m/z 450.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ ppm 7.05 (t, J=7.63 Hz, 1H) 7.00 (br.s., 1H) 6.87-6.94 (m, 2H) 4.26 (s, 2H) 3.46 (t, J=5.67 Hz, 2H) 2.95 (d,J=6.06 Hz, 1H) 2.87-2.93 (m, 2H) 2.66-2.74 (m, 2H) 1.12 (d, J=6.26 Hz,3H).

Example 583-(5-fluoro-2-(2-fluoro-5-(trifluoromethoxy)phenyl)-7-methyl-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid

Step A. ethyl3-(5-fluoro-2-(2-fluoro-5-(trifluoromethoxy)phenyl)-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of ethyl3-(5-fluoro-7-methyl-1,2,3,4-tetra-hydro-isoquinolin-6-yl)propanoate(Intermediate 48, 100 mg, 0.377 mmol) and2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (117 mg, 0.452 mmol) indioxane (3 mL) were added Xphos-precatalyst (32 mg, 0.039 mmol) andCs₂CO₃ (368 mg, 1.131 mmol). The mixture was stirred at 90° C. for 16 h.Then water (100 mL) was added. The mixture was extracted with EtOAc(2×50 mL), washed with water (200 mL), dried over anhydrous Na₂SO₄filtered, concentrated in vacuo and purified by silica gel columnchromatography (PE/EtOAc=50:1 to 20:1) to give the title compound. ESIMS m/z 444.1 [M+H]⁺.

Step B.3-(5-fluoro-2-(2-fluoro-5-(trifluoromethoxy)phenyl)-7-methyl-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid. To a solution of ethyl3-(5-fluoro-2-(2-fluoro-5-(trifluoromethoxy)-phenyl)-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(127 mg, 0.286 mmol) in THF (6 ml) and water (3 ml) was added LiOHhydrate (12 mg, 0.286 mmol). The mixture was stirred at 20° C. for 2 h,then acidified with HCl (6 N, about 3 mL). The mixture was extractedwith EtOAc (2×20 mL), washed with water (20 mL), dried over anhydrousNa₂SO₄, and evaporated. The crude product was purified with a PhenomenexSynergi C18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CNas eluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN, Detector wavelength: 220 nm.) followed by concentration to obtainthe title compound. ¹H NMR (400 MHz, CDCl₃) ppm δ 2.33 (s, 3H) 2.55-2.64(m, 2H) 2.91 (t, J=5.51 Hz, 2H) 2.98 (t, J=7.83 Hz, 2H) 3.44 (t, J=5.84Hz, 2H) 4.22 (s, 2H) 6.74 (s, 1H) 6.76-6.85 (m, 2H) 7.04 (dd, J=11.80,8.71 Hz, 1H); ESI MS m/z 416.1 [M+H]⁺

Example 593-(2-(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid

Step A. Ethyl3-(2-(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoateA solution of ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (53 mg, 0.211mmol), 4-bromo-3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazole (60 mg,0.175 mmol) in dioxane (1.00 mL) was treated with Xantphos (30 mg, 0.035mmol) and Cs₂CO₃ (170 mg, 0.525 mmol), and then heated at 100° C. for 16h. The mixture was concentrated under reduced pressure to give aresidue, which was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm)followed by concentration (below 50° C.) to obtain to the titlecompound.

Step B.3-(2-(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid. To a solution of ethyl3-(2-(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(1 mg, 1.950 μmol) in THF (1 ml), EtOH (1 ml) and water (0.5 ml), wasadded LiOH hydrate (1 mg, 0.024 mmol). The mixture was stirred at 30° C.for 15 h. After acidification with 1N HCl to pH=2, the solvent wasremoved under reduced pressure. The residue was purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250*21.2 mm*4 μm) using water (0.2% Formic acid) and CH₃CN aseluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN, Detector wavelength: 220 nm) followed by concentration (below 50°C.) to obtain the title compound. m/z 485.1 [M+H]⁺: ¹H NMR (400 MHz,CDCl₃) δ ppm 7.80 (d, J=8.60 Hz, 2H) 7.25 (d, J=8.38 Hz, 2H) 6.90-6.98(m, 1H) 6.58 (d, J=7.94 Hz, 1H) 4.05 (s, 2H) 3.30 (t, J=5.51 Hz, 2H)2.88-2.95 (m, 2H) 2.75-2.83 (m, 2H) 2.61-2.68 (m, 2H).

Example 603-(2-(5-(cyclobutylmethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid

Step A-ethyl3-(2-(5-(cyclobutylmethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoate:To a solution of ethyl3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoate (100 mg,0.398 mmol) in dioxane (6 mL) was added2-bromo-4-(cyclobutylmethyl)-1-fluorobenzene (Intermediate 41, 97 mg,0.398 mmol), Cs₂CO₃ (389 mg, 1.194 mmol) and XPHOS-precatalyst (32 mg,0.041 mmol). The reaction mixture was placed under a N₂ atmosphere andheated to 90° C. for 18 h. The solvent was removed in vacuo and theresulting mixture was diluted with water (20 mL) and extracted withEtOAc (2×20 mL), dried, filtered and the concentrated in vacuo. Thecrude product was purified by silica gel chromatography (PE/EtOAc=40:1)to give the title compound. m/z 414.1[M+H]⁺.

Step-B.3-(2-(5-(cyclobutylmethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid. To a solution of ethyl3-(2-(5-(cyclobutylmethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(80 mg, 0.193 mmol) in THF (4 mL) and water (2 mL) was added LiOHhydrate (40 mg, 0.953 mmol). Then the reaction mixture was stirred at rtfor 18 h. The mixture was acidified to pH˜2 with HCl (0.7 mL, 1 N) andconcentrated in vacuo. The crude product was purified by reverse phaseHPLC on a GILSON 281 instrument fitted with a Phenomenex Synergi C18(250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CN as eluents(Mobile phase A: water (0.2% Formic acid), Mobile phase B: CH₃CN,Detector wavelength: 220 nm) followed by concentration to give the titlecompound. ¹HNMR (400 MHz, ppm) δ 7.04 (t, J=7.65 Hz; 1H), 6.97 (dd,J=12.05, 8.28 Hz, 1H), 6.80-6.91 (m, 3H), 4.25 (s, 2H), 3.42 (t, J=5.90Hz, 2H), 2.89-3.00 (m, 5H), 2.69 (t, J=7.78 Hz, 2H), 2.02-2.09 (m, 2H),1.76-1.84 (m, 2H), 1.66-1.73 (m, 2H), 1.50-1.60 (m, 2H). m/z 386.2[M+H]⁺.

Example 613-(2-(5-cyclobutoxy-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)-propanoicacid

Step A-(E)-ethyl 3-(6-chloroquinolin-2-yl)acrylate: To a solution of6-bromo-5-fluoroisoquinoline (210 mg, 0.929 mmol) in dry 1,4-dioxane (10ml) was added tri-tert-butyl-phosphonium tetrafluoroborate (51 mg, 0.176mmol), dicyclohexylamine (253 mg, 1.394 mmol), and ethyl acrylate (112mg, 1.115 mmol). Then the mixture was degassed for 5 min with N₂. ThenPd₂(dba)₃ (85 mg, 0.093 mmol) was added. The final mixture was heated to100° C. and stirred for 18 h in a N₂ atmosphere. The reaction mixturewas diluted with EtOAc (20 mL). The solid was filtered off, and thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatography (PE/EtOAc=20:1 to 3:1) to afford the title compound.

Step B. ethyl 3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of (E)-ethyl 3-(5-fluoroisoquinolin-6-yl)acrylate (220 mg,0.897 mmol) in MeOH (20 ml) was added platinum (IV) oxide (40 mg, 0.176mmol). The reaction mixture was stirred under 50 psi of hydrogenatmosphere at 30° C. for 5 hours. The mixture was filtered, and thefiltrate was concentrated in vacuo to give the title compound.

Step C. Ethyl3-(2-(5-cyclobutoxy-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoate. To a solution of ethyl3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoate (100 mg,0.398 mmol) in 1,4-dioxane (5 ml) was added2-bromo-4-cyclobutoxy-1-fluoro benzene (117 mg, 0.478 mmol), Cs₂CO₃ (194mg, 0.597 mmol), XANTPHOS (46 mg, 0.080 mmol) and Pd₂(dba)₃ (36 mg,0.039 mmol). Then the reaction mixture was placed under nitrogen andstirred for 20 min at 100° C. under microwave. The mixture wasconcentrated in vacuo, then water (10 mL) was added and extracted withEtOAc (2×10 mL). The combined organic layers were concentrated in vacuo,and the crude product was purified by silica gel preparative TLC(PE/EtOAc=2:1) to give the title compound.

Step D.3-(2-(5-cyclobutoxy-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid: To a solution of ethyl3-(2-(5-cyclobutoxy-2-fluoro-phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(20 mg, 0.048 mmol) in THF (2.00 mL), MeOH (2.00 mL) and water (1.00 mL)was added LiOH (6 mg, 0.251 mmol). Then the reaction mixture was stirredat rt for 3 h. The mixture was acidified with HCl (0.5 mL, 6 N) andconcentrated in vacuo. The crude product was purified by reverse phaseHPLC on a GILSON 281 instrument fitted with a Phenomenex Synergi C18(250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CN as eluents(Mobile phase A: water (0.2% Formic acid), Mobile phase B: CH₃CN,Detector wavelength: 220 nm) followed by concentration to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 6.97 (t, J=7.4 Hz, 1H), 6.86 (dd,J=8.8, 11.9 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.45-6.38 (m, 1H),6.28-6.21 (m, 1H), 4.52-4.44 (m, 1H), 4.16 (s, 2H), 3.35 (t, J=5.7 Hz,2H), 2.94-2.80 (m, 4H), 2.61 (t, J=7.0 Hz, 2H), 2.37-2.28 (m, 2H),2.11-2.01 (m, 2H), 1.77 (d, J=10.2 Hz, 1H), 1.64-1.56 (m, 1H). m/z=388.1[M+H]⁺.

The examples in Table 2 were prepared from the appropriate startingmaterials described previously or commercially available startingmaterials available using procedures described in Examples 56-61.

TABLE 2 Example Structure Name [M + H]⁺ 62

3-(2-{3-chloro-2- fluoro-5-[(5-methyl- 1,3-thiazol-2-yl) oxy]phenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoic acid 465.0 63

3-{2-[6-(cyclobutyloxy)- 3-fluoro-pyridin-2-yl]- 5-fluoro-1,2,3,4-tetra-hydro-isoquinolin- 6-yl}propanoic acid 389.1 64

3-{2-[5-(cyclobutyloxy)- 2,3-difluorophenyl]-5- fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl} propanoic acid 406.1 65

3-{2-[3-chloro-2-fluoro- 5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetra- hydroisoquinolin-6-yl} propanoic acid 436.0 66

3-(2-{2,3-difluoro-5-[(trans- 3-methoxycyclobutyl) oxy]phenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl)-propanoic acid 436.1 67

3-(2-{5-[cyclobutyl (difluoro)-methyl]- 2-fluorophenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl)-propanoic acid 422.1 68

3-{2-[3-chloro-2-fluoro- 5-(trifluoromethoxy) phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}- 2-methyl- propanoic acid 450.0 69

3-{2-[3-chloro-2-fluoro-5- (trifluoromethoxy)phenyl]- 5-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}-2-methyl- propanoic acid 450.1 70

3-{5-fluoro-2-[2-fluoro- 5-(trifluoromethoxy)phenyl]- 7-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl}-propanoic acid 416.1 71

3-{2-[4-chloro-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl}-propanoic acid 428.1 72

3-{5-chloro-2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroiso- quinolin-6-yl} propanoic acid 418.1 73

3-{2-[3-(4-chlorophenyl)- 5-(trifluoromethyl) isothiazol-4-yl]-5-fluoro-1,2,3,4- tetrahydroisoquino- lin-6-yl}-propanoic acid 485.1 74

3-{2-[5-(cyclobutylmethyl)- 2-fluorophenyl]- 5-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 386.2 75

3-[2-(5-{[3-(difluoromethyl) cyclobutyl]oxy}- 2,3-difluorophenyl)-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl]-propanoic acid 456.1 76

3-{2-[2-cyano- 5-(cyclobutyloxy)- phenyl]-5-fluoro- 1,2,3,4-tetrahydro-isoquinolin-6-yl} propanoic acid 395.1 77

3-{5-fluoro-2-[2-fluoro- 5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro- isoquinolin-6-yl}- 2-methyl-propanoic acid 416.1 78

3-{2-[2-cyano- 5-(trifluoromethoxy) phenyl]-5-fluoro-1,2,3,4-tetrahydro- isoquinolin-6-yl} propanoic acid 409.1 79

3-(2-(2-cyano-5- cyclobutoxy-3- fluorophenyl)-5-fluoro- 1,2,3,4-tetrahydroisoquinolin- 6-yl)-2-methyl-propanoic acid 425.1 80

3-{5-fluoro-2-[2-fluoro- 5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro- isoquinolin-6-yl} propanoic acid 402.0 81

3-{2-[5-(cyclobutyloxy)- 2-fluorophenyl]- 5-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 388.1 82

3-{2-[2-cyano- 5-(cyclobutyloxy)-3- fluorophenyl]- 1,2,3,4-tetrahydro-isoquinolin- 6-yl}propanoic acid 395.0

Example 83(1S,2S)-2-(2-(2,3-difluoro-5-((1R,3S)-3-methylcyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid

Step A. (1S,2S)-ethyl2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate.To a solution of 2,3-difluoro-5-((1R,3R)-3-methylcyclobutoxy)phenyltrifluoromethanesulfonate (200 mg, 0.578 mmol) in dioxane (4 mL) wereadded (1S,2S)-ethyl2-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-cyclopropanecarboxylate (156 mg,0.635 mmol), Cs₂CO₃ (565 mg, 1.733 mmol) and RUPHOS precatalyst (94 mg,0.116 mmol). After the addition was complete, the mixture was stirredunder argon at 90° C. for 15 h. The reaction mixture was filtered,washed with water (2×20 mL), extracted with EtOAc (3×20 mL). Thecombined organic layers were evaporated in vacuo to give crude product,which was further purified by silica gel preparative TLC (PE:EtOAc=10:1as elute) to give the title compound. ESI MS m/z=442.1 [M+1]⁺.

Step B.(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid. To a solution of (1S,2S)-ethyl2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-cyclopropanecarboxylate(20 mg, 0.045 mmol) in MeOH (2 mL), THF (2 mL) and water (1 mL) wasadded LiOH hydrate (10 mg, 0.238 mmol) and stirred at rt for 15 h. Themixture was acidified by the diluted hydrochloride acid (1N) to pH˜2.The mixture was concentrated in vacuo to give crude product. The crudeproduct was further purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm),then concentrated on a lyophilizer to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.04 (d, J=7.78 Hz, 1H). 6.88-6.98 (m, 2H), 6.12-6.24(m, 2H), 4.66 (t, J=6.15 Hz, 1H), 4.27 (s, 2H), 3.45 (t, J=5.77 Hz, 2H),2.94 (t, J=5.52 Hz, 2H); 2.53-2.63 (m, 1H), 2.40-2.52 (m, 1H), 2.25-2.34(m, 2H), 2.02-2.10 (m, 2H), 1.89 (dt, J=8.34, 4.49 Hz, 1H), 1.65 (dt,J=9.54, 4.77 Hz, 1H), 1.36-1.45 (m, 1H), 1.19 (d, J=7.03 Hz, 3H); ESI MSm/z=414.1.

Example 842-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-cyclopropanecarboxylicacid

Step A. tert-butyl 6-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate: Toa stirred solution of tert-butyl6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.5 g, 4.80 mmol) inTHF (30 mL) was added 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane (0.740g, 4.80 mmol), triphenylphosphine (1.260 g, 4.80 mmol) and potassium2-methyl-propan-2-olate (0.027 g, 0.240 mmol). The mixture was stirredat 67° C. for 24 h. The mixture was washed with water (2×10 mL) andextracted with EtOAc (2×30 mL). The extract was dried over by Na₂SO₄filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (PE:EtOAc=20:1) to give the title compound.

Step B. 6-vinyl-1,2,3,4-tetrahydroisoquinoline hydrochloride. A solutionof tert-butyl 6-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (970 mg,3.74 mmol) in HCl-EtOAc (10 mL) was stirred at rt for 1 h. The mixturewas then evaporated under reduce pressure to give the crude titlecompound.

Step C.2-(2-fluoro-5-(trifluoromethoxy)phenyl)-6-vinyl-1,2,3,4-tetrahydro-isoquinoline.To a stirred solution of 6-vinyl-1,2,3,4-tetrahydroisoquinolinehydrochloride (732 mg, 3.74 mmol) in 1,4-dioxane (30 mL) was added2-bromo-1-fluoro-4-(trifluoromethoxy)benzene (969 mg, 3.74 mmol), Cs₂CO₃(2438 mg, 7.48 mmol), XANTPHOS (433 mg, 0.748 mmol) and Pd₂(dba)₃ (343mg, 0.374 mmol). The mixture was stirred at 90° C. for 18 h. The mixturewas washed with water (10 mL×2) and extracted with EtOAc (30 mL×2). Theextract was dried over by Na₂SO₄ and concentrated in vacuo. The residuewas purified by silica gel column chromatography (PE:EtOAc=40:1) to givethe title compound.

Step D. ethyl2-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)cyclopropanecarboxylate.To a solution of2-(2-fluoro-5-(trifluoro-methoxy)phenyl)-6-vinyl-1,2,3,4-tetrahydroisoquinoline(60 mg, 0.178 mmol) in DCM (10 mL) was added CuI (7 mg, 0.037 mmol) andthe mixture was stirred for 5 min. Then ethyl 2-diazoacetate (61 mg,0.535 mmol) in DCM (10 mL) was added dropwise slowly and the reactionwas stirred at rt for overnight (18 h). The mixture was washed withwater (10 mL×2) and extracted with DCM (30 mL×2). The extract was driedover by Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel PTLC (PE:EtOAc=10:1) to give the title compound.

Step E.2-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid: To a stirred solution of ethyl2-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate(30 mg, 0.071 mmol) in THF (4 mL) and water (2 mL) was added LiOH—H₂O (6mg, 0.143 mmol) and the mixture was stirred at rt for 2 h. The mixturewas diluted with water and extracted with EtOAc (2×30 mL). The extractwas dried (Na₂SO₄) filtered, and concentrated in vacuo. The residue waspurified by reverse phase HPLC on a GILSON 281 instrument fitted with aPhenomenex Synergi C18 (250×21.2 mm×4 μm) using water (0.2% Formic acid)and CH₃CN as eluents (Mobile phase A: water (0.2% Formic acid), Mobilephase B: CH₃CN, Detector wavelength: 220 nm) followed by concentration(below 50° C.) to give the title compound. ¹HNMR (400 MHz, CDCl₁₋₆) δ(400 MHz, ppm): 7.00-7.10 (m, 2H) 6.90-6.98 (m, 2H) 6.83 (d, J=6.65 Hz,1H) 6.78 (d, J=8.61 Hz, 1H) 4.28 (s, 2H) 3.46 (t, J=5.67 Hz, 2H) 2.98(t, J=5.09 Hz, 2H) 2.59 (br. s., 1H) 1.91 (br. s., 1H) 1.62-1.71 (m, 1H)1.41 (d, J=3.52 Hz, 1H). m/z 369.1 [M+H]⁺.

The examples in Table 3 were prepared from the appropriate startingmaterials described previously or commercially available startingmaterials available using procedures described in Examples 83-81.

TABLE 3 Example Structure IUPAC Name [M + H]+  85

(1R,2R)-2-{2-[5- (cyclobutyloxy)-2,3- difluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane- carboxylic acid 400.1  86

(1R,2R)-2-{2-[3-chloro- 5-(cyclobutyloxy)- 2-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane carboxylic acid 416.1  87

(1R,2,R)-2-{2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane carboxylic acid 396.1  88

(1S,2S)-2-{2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane carboxylic acid 396.1  89

(1R,2R)-2-(2-{3-cyano- 2-fluoro-5-[(trans-3- methoxycyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl) cyclopropanecarboxylicacid 437.2  90

(1S,2S)-2-{2-[2-fluoro- 5-(trifluoromethoxy) benzyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane carboxylic acid 410.4  91

(1S,2S)-2-{2-[3-chloro- 5-(cyclobutyloxy)-2- fluorophenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane carboxylic acid 416.1  92

2-{2-[4-fluoro-1-(4- fluorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclo- propanecarboxylic acid 410.1  93

(1S,2S)-2-{2-[3-chloro-2- fluoro-5-(trifluoromethyl) benzyl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropanecarboxylic acid 428.1  94

2-{2-[4-fluoro-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclo- propanecarboxylic acid 406.2  95

2-{2-[4-fluoro-1-(4- fluorophenyl)-3-methyl- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclo- propanecarboxylic acid 410.1  96

2-{2-[4-fluoro-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropanecarboxylic acid 406.2  97

(1S,2S)-2-(2-{2-cyano- 3-methoxy-5-[(trans-3- methoxycyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl) cyclopropanecarboxylicacid 449.2  98

(1S,2S)-2-(2-{2,3-difluoro- 5-[(trans-3-methylcyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl)- cyclopropanecarboxylicacid 414.1  99

(1R,2R)-2-(2-{2,3-difluoro- 5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl)- cyclopropanecarboxylicacid 430.2 100

(1S,2S)-2-(2-{2,3-difluoro- 5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl)- cyclopropanecarboxylicacid 430.2 101

(1R,2R)-2-(2-{2,3-difluoro- 5-[(trans-3-methylcyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl)- cyclopropanecarboxylicacid 414.1 102

2-{2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropanecarboxylic acid 396.1 103

(1R,2R)-2-(2-{2-cyano- 3-fluoro-5-[(trans-3- methoxycyclobutyl)oxy]phenyl}-1,2,3,4- tetrahydroisoquinolin-6-yl) cyclopropanecarboxylicacid 437.1 104

2-{2-[3-chloro- 2-fluoro-5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropane- carboxylic acid 430.1 105

2-{2-[3-chloro- 2-fluoro-5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoqninolin-6-yl} cyclopropane- carboxylic acid 430.1

Example 106(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methoxycyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)cyclopropanecarboxylicacid

Step A. (1S,2S)-ethyl2-(2-(2,3-difluoro-5-((1r,3S)-3-methoxycyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate.To a solution of 2,3-difluoro-5-((1r,3r)-3-methoxycyclobutoxy)phenyltrifluoromethanesulfonate (200 mg, 0.552 mmol) and(1S,2S)-ethyl-2-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropane-carboxylate (160 mg, 0.607 mmol) in 1,4-dioxane (10 ml)were added Cs₂CO₃ (540 mg, 1.656 mmol) and Ruphos-precatalyst (90 mg,0.110 mmol). The mixture was stirred at 100° C. for 15 h under N₂. Themixture was filtered and concentrated in vacuo to give the crudeproduct, which was purified by silica gel PTLC (PE:EA=5:1) to give thetitle compound. m/z 476.3 [M+H]⁺.

Step B.(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methoxycyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid: To a solution of (1S,2S)-ethyl2-(2-(2,3-difluoro-5-((1r,3S)-3-methoxycyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate(40 mg, 0.084 mmol) in MeOH (2 ml), THF (2 ml) and water (1 mL) wasadded LiOH hydrate (11 mg, 0.262 mmol), then the mixture was stirred at20° C. for 15 h. The reaction mixture was acidified with 1N HCl to pH 5and extracted with EtOAc (3×20 mL). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm),followed by concentration (below 50° C.) to obtain the title compound.¹H NMR (400 MHz, CDCl₃) δ 6.77-6.87 (m, 1H), 6.13-6.22 (m, 1H), 4.71 (t,J=4.70 Hz, 1H), 4.24 (s, 2H), 4.07-4.14 (m, 1H), 3.45 (t, J=5.48 Hz,2H), 3.27 (s, 3H), 2.92 (br. s., 2H), 2.71 (br. s., 1H), 2.33-2.45 (m,4H), 1.87-1.95 (m, 1H), 1.61-1.70 (m, 1H), 1.38-1.48 (m, 1H); m/z=448.2[M+H]⁺.

Example 107(1S,2S)-2-(2-(3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid

Step A. (1S,2S)-ethyl2-(2-(3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate:To a solution of (1S,2S)-ethyl2-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate(200 mg, 0.760 mmol) in 1,4-dioxane (20 mL) was added Cs₂CO₃ (495 mg,1.519 mmol), 3-bromo-2-fluoro-5-(trifluoromethoxy)benzonitrile(Intermediate 44, 350 mg, 1.232 mmol), Pd₂(dba)₃ (696 mg, 0.760 mmol)and XANTPHOS (440 mg, 0.760 mmol). The mixture was stirred at 100° C.under N₂ overnight (15 h). The mixture was filtered, concentrated undervacuum and dissolved with EtOAc (2×50 mL). The combined organic layerwas washed with brine (2×30 mL), and then dried over Na₂SO₄, filteredand concentrated in vacuo to give crude (1S,2S)-ethyl2-(2-(3-cyano-2-fluoro-5-(trifluoro-methoxy)-phenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)cyclopropanecarboxylate.The crude product was purified by silica gel chromatography (PE/EtOAc30:1-20:1) to give the title compound.

Step B.(1S,2S)-2-(2-(3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid. To a solution of (1S,2S)-ethyl2-(2-(3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate(88 mg, 0.189 mmol) in THF (5 mL) and water (2.5 mL) was added LiOH—H₂O(20 mg, 0.477 mmol) and the mixture was stirred at 20° C. for 15 h. Themixture was concentrated in vacuo to give crude product. The crudeproduct was purified by reverse phase HPLC on a GILSON 281 instrumentfitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) using water(0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water (0.2%Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm)followed by concentration (below 50° C.) to give the title compound.¹HNMR (400 MHz, CH₃OD) δ ppm 7.31-7.22 (m, 2H) 6.99-6.86 (m, 2H) 4.35(s, 2H) 3.54 (t, J=5.77 Hz, 2H) 3.00-2.90 (m, 2H) 2.62-2.52 (m, 1H)1.90-1.75 (m, 1H) 1.52 (dt, J=9.29, 4.89 Hz, 1H) 1.44-1.36 (m, 1H). MS(ESI) m/z 439.1 (M+H)⁺.

Example 108(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)cyclopropanecarboxylicacid

Step A-(1S,2S)-ethyl2-(2-(2,3-difluoro-5-((1R,3S)-3-methylcyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate:To a solution of 2,3-difluoro-5-((1R,3R)-3-methylcyclobutoxy)phenyltrifluoromethanesulfonate (Intermediate 9, 200 mg, 0.578 mmol) indioxane (5 mL) were added2-(((1S,2S)-2-(5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)cyclopropanecarbonyl)oxy)ethan-1-ylium (167 mg, 0.635 mmol), Cs₂CO₃ (565mg, 1.733 mmol) and RUPHOS precatalyst (94 mg, 0.116 mmol). After theaddition was complete, the mixture was stirred at 90° C. for 15 h. Themixture was filtered and filtrate was diluted with water (30 ml), andextracted with EtOAc (3×30 mL). The combined organic layer wasconcentrated in vacuo and the residue was purified by silica gel PTLC(PE:EtOAc=10:1), to give the title compound. m/z 460.1 [M+1]⁺.

Step-B.(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid. To a solution of (1S,2S)-ethyl2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylate(20 mg, 0.038 mmol) in MeOH (2 mL), THF (2 mL) and water (1 mL) wasadded LiOH hydrate (10 mg, 0.238 mmol). After the addition was complete,the mixture was stirred at rt for 15 h. The mixture was acidified byhydrochloride acid (1N) to pH˜2, and concentrated in vacuo to give crudeproduct, which was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detector wavelength: 220 nm)then freeze dried to afford the title compound. ¹H NMR (400 MHz, CDCl₃)δ 6.76-6.88 (m, 2H), 6.14-6.25 (m, 2H), 4.66 (dt, J=12.42, 6.11 Hz, 1H),4.25 (s, 2H), 3.45 (t, J=5.67 Hz, 2H), 2.89-2.97 (m, 2H), 2.72 (t,J=9.78 Hz, 1H), 2.46 (br. s., 1H), 2.25-2.33 (m, 2H), 2.03-2.10 (m, 2H),1.91 (dt, J=8.22, 4.50 Hz, 1H), 1.66 (dt, J=9.29, 4.55 Hz, 1H),1.39-1.47 (m, 1H), 1.13-1.23 (m, 3H); m/z 432.4 [M+1]⁺.

The examples in Table 4 were prepared from the appropriate startingmaterials described previously or commercially available startingmaterials available using procedures described in Examples 106-108.

TABLE 4 Example Structure Name [M + H]⁺ 109

(1R,2R)-2-{2-[3-cyano- 2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl}cyclopropane-carboxylic acid 439.1 110

(1R,2R)-2-(2-{2,3-difluoro- 5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl)-cyclopropanecarboxylic acid 448.2 111

(1R,2R)-2-{2-[3-chloro- 2-fluoro-5-(trifluoromethoxy)-phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl}cyclo-propanecarboxylic acid 448.0 112

(1R,2R)-2-(2-{2,3- difluoro-5-[(trans-3- methylcyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 432.4 113

(1R,2R)-2-{5-fluoro-2-[2- fluoro-5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropane-carboxylic acid 414.1 114

(1R,2R)-2-{2-[3-chloro- 5-(cyclobutyloxy)- 2-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropanecarboxylic acid 416.1 115

(1S,2S)-2-(2-{2,3-difluoro- 5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl)-cyclopropanecarboxylic acid 448.2 116

(1S,2S)-2-{2-[3-cyano-2- fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl}cyclopropane-carboxylic acid 439.1 117

(1S,2S)-2-{2-[2-cyano- 5-(trifluoromethoxy)phenyl]- 5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropane- carboxylic acid 421.1 118

(1S,2S)-2-{5-fluoro- 2-[2-fluoro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl} cyclopropane- carboxylicacid 414.1 119

(1S,2S)-2-{2-[2-cyano-3- fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl}cyclopropane-carboxylic acid 439.0 120

(1S,2S)-2-{2-[3-chloro-2- fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl}cyclopropane-carboxylic acid 448.0 121

(1R,2R)-2-{2-[2-chloro-3- fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl}cyclo-propanecarboxylic acid 448.0 122

(1S,2S)-2-(2-{2,3-difluoro- 5-[(trans-3-methylcyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl)cyclopropanecarboxylic acid 432.4 123

(1R,2R)-2-{2-[3-chloro- 5-(cyclobutyloxy)- 2-fluorophenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl} cyclopropane- carboxylicacid 434.1 124

(1S,2S)-2-{2-[2-chloro-3- fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin-6-yl}cyclopropanecarboxylic acid 448.0 125

(1S,2S)-2-{2-[3-chloro- 5-(cyclobutyloxy)-2- fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane- carboxylic acid 434.1126

(1S,2S)-2-{2-[2-cyano- 5-(cyclobutyloxy)-3- fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}cyclopropane- carboxylic acid 425.1

Example 1275-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)pentanoicacid

Step A. 2-(tert-butyl) 6-methyl3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate. A stirred mixture oftert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (21 g, 67.5mmol) in MeOH (300 mL), was added Pd(dppf)Cl₂ (4.9 g, 6.75 mmol) and TEA(20.45 g, 202 mmol). The mixture was stirred at 110° C. for 48 h underhigh pressure CO (2 MPa). Then the catalyst and salt were filtered offand the filtrate was concentrated in vacuo. followed by purification bysilica gel chromatography (PE/EtOAc=50:1 to 6:1) to afford the titlecompound.

Step B. tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. A solutionof 2-tert-butyl 6-methyl 3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate(15 g, 51.5 mmol) in THF (80 mL) was added dropwise to a solution of LAH(2.94 g, 77.32 mmol) in THF (80 mL) at −78° C. The reaction mixture wasstirred at −78° C. for 2 h. The mixture was quenched with H₂O, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (PE/EtOAc=20:1-3:1) to give thetitle compound.

Step C. Tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. Astirred mixture of tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (8.0 g, 30.4mmol) in DCM (100 mL) was added MnO₂ (21.2 g, 243.8 mmol). The mixturewas stirred under reflux for 16 h. The mixture was filtered andconcentrated in vacuo, the crude product was purified by silica gelchromatography (PE/:EtOAc=100:1˜10:1) to afford the title compound.

Step D. 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. A solutionof tert-butyl-6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.044mg, 4 mmol) in HCl-MeOH (50 mL) was stirred under reflux for 16 h. Themixture was evaporated to obtain the title compound.

Step E.5-(6-formyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile.To a solution of methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate(197 mg, 1 mmol), in 1,4-dioxane was added5-iodo-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile (323 mg, 1 mmol),Pd₂(dba)₃ (92 mg, 0.1 mmol), XANTPHOS (173 mg, 0.3 mmol) and Cs₂CO₃ (815mg, 3 mmol). The reaction mixture was stirred under N₂ and heated to100° C. for 15 h. The mixture was quenched with H₂O, then extracted withEtOAc, the organic layer was washed with brine, dried over Na₂SO₄,concentrated in vacuo an purified by silica gel PTLC (PE:EA=3:1) to givethe title compound.

Step F. (2E,4E)-methyl5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetra-hydroisoquinolin-6-yl)penta-2,4-dienoateA stirred mixture of ethyl methyl 4-(diethoxyphosphoryl)but-2-enoate (53mg, 0.21 mmol) in THF (2 mL) was added NaH (12 mg, 0.28 mmol) at 0° C.The mixture was stirred for at 0° C. for 45 min, and then5-(6-formyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile(68 mg, 0.19 mmol) was added. The mixture was stirred at rt for 15 h.The mixture was poured into a solution of sat. NH₄Cl (10 mL) andextracted with EtOAc (10 mL×3). The organic layer was separated, washedwith brine, dried and evaporated to obtain the title compound.

Step G. Methyl5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetra-hydroisoquinolin-6-yl)pentanoate.To a stirred mixture of (2E,4E)-methyl5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-iso-quinolin-6-yl)penta-2,4-dienoate(80 mg, 0.182 mmol) in DCM (4 mL) was added Pd/C (20 mg). The reactionwas stirred under a hydrogen atmosphere at room temperature for 6 hours.Then the reaction mixture was filtered and concentrated in vacuo toobtain the title compound.

Step H.5-(6-formyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile-5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pentanoicacid. To a solution of methyl5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pentanoate(70 mg, 0.160 mmol) in THF (2 mL), MeOH (2 mL) and (1 mL) was addedLiOH—H₂O (44 mg, 0.8 mmol). The reaction mixture was stirred at rtovernight. The mixture was acidified with HCl, and then extracted withEtOAc. The organic layer was separated, and evaporated to give the crudeproduct, which was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250*21.2 mm*4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN. Detective wavelength: 220nm.) followed by concentration (below 50° C.) to obtain the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ=7.44 (d, J=8.2 Hz, 2H), 7.22 (d,J=8.2 Hz, 2H), 7.05-6.79 (m, 3H). 4.43 (s, 2H), 3.36 (t, J=5.9 Hz, 2H),2.75 (t, J=5.5 Hz, 2H), 2.63-2.51 (m, 2H), 2.36 (d, J=11.7 Hz, 8H), 1.67(d, J=3.1 Hz, 4H). m/z 439.2 [M+H]⁺.

Example 1285-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)hexanoicacid

Step A. tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate.To a solution of pyridine (16.22 ml, 201 mmol) and tert-butyl6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (50.0 g, 201 mmol)in DCM (600 ml), Tf₂O (33.9 ml, 201 mmol) was added dropwise at 0° C.and the mixture was stirred at 0° C. for 1 h. The reaction mixture wasdiluted with DCM (800 mL), washed with water (2×200 mL) and brine (2×200mL). The organic solution was dried, filtered, concentrated in vacuo andpurified by silica gel chromatography (PE:EtOAc=80: 1-10:1) to give thetitle compound.

Step B. 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)ethanone hydrochloride: Toa solution of 1-(vinyloxy)butane (1.576 g, 15.73 mmol), tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.0 g, 2.62 mmol) in DMF (15 ml) was added Pd(OAc)₂ (0.059 g, 0.262mmol) and 1,3-bis(diphenylphosphino)propane (0.108 g, 0.262 mmol), themixture was stirred at 80° C. for 15 h. The reaction was quenched withwater (25 mL), extracted with EtOAc (3×45 mL). The organic layer wasseparated, washed with water (3×25 mL) and brine (3×25 mL), concentratedand purified by silica gel chromatography (PE:EtOAc=20:1-5:1) to givetert-butyl 6-acetyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. Asolution of tert-butyl6-acetyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.5 g, 1.816 mmol)in HCl-MeOH (15 ml) was stirred at 20° C. for 1 h. Then the reactionmixture was concentrated to give the crude title compound, which wasused directly in the next step without further purification.

Step C.5-(6-acetyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile:A solution of potassium fluoride (0.663 g, 11.41 mmol),5-iodo-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile (1.844 g, 5.71mmol) and 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)ethanone (1.00 g, 5.71mmol) in DMSO (15 ml) was stirred at 110° C. for 15 h. The reaction wasquenched with water, extracted with EtOAc (3×30 mL). The organic layerswere washed with water (2×15 mL) and brine (2×15 mL), dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo and purified bysilica gel chromatography (PE:EtOAc=30:1˜3:1) to give the titlecompound.

Step D. (2E,4E)-methyl5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)hexa-2,4-dienoate.To a suspension of NaH (52 mg, 1.300 mmol) in THF (3 ml) was added(E)-methyl 4-(dimethoxyphosphoryl)but-2-enoate (270 mg, 1.296 mmol) at0° C., and the mixture was stirred at 0° C. for 0.5 h. Then a solutionof5-(6-acetyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile(400 mg, 1.080 mmol) in THF (3 mL) was added dropwise to the abovemixture. The reaction mixture was stirred at 0-20° C. for 6 h. Thereaction was quenched with a solution of sat. NH₄Cl, extracted withEtOAc (3×25 mL). The combined organic layers were washed with water(2×15 mL) and brine (2×15 mL), concentrated in vacuo and purified bysilica gel chromatography (PE:EtOAc=20:1˜5:1) to give the titlecompound.

Step E.(2E,4E)-5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)hexa-2,4-dienoicacid: To a solution of(2E,4E)-methyl-5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)hexa-2,4-dienoate (200 mg, 0.442 mmol) and LiOH hydrate (56 mg, 1.334mmol) in THF (2.0 ml)/MeOH (2.0 ml)/Water (2.0 ml). The reaction mixturewas stirred at 20° C. for 3 h. Then the reaction mixture wasconcentrated to give a residue, which was diluted with HCl (1 N. 5 mL)and extracted with EtOAc (3×15 mL). The combined organic layers werewashed with water (2×5 mL) and brine (2×5 mL). The organic solution wasdried over Na₂SO₄, filtered, and the filtrate was concentrated to givethe title compound.

Step F.5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-isoquinolin-6yl)hexanoic acid. To a solution of(2E,4E)-5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)hexa-2,4-dienoicacid (180 mg, 0.410 mmol) in MeOH (5 ml) was added Pd—C (20 mg, 0.188mmol), and the reaction was stirred at 10° C. for 15 h under H₂ balloon.The reaction mixture was filtered, the organic layer was concentrated invacuo to give a residue, which was purified by reverse phase HPLC on aGILSON 281 instrument fitted with a Phenomenex Synergi C18 (250*21.2mm*4 μm) using water (0.2% Formic acid) and CH₃CN as eluents (Mobilephase A: water (0.2% Formic acid), Mobile phase B: CH₃CN, Detectivewavelength: 220 nm) followed by concentration to give to give the titlecompound as a racemic mixture. The enantiomers of5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)-hexanoicacid (160 mg) were purified by SFC (Instrument: MG-II; Column: ChiralcelOJ 250×30 mm I.D., 5 um; Mobile phase: Supercritical CO₂/MeOH (0.1%)NH₃.H₂O=75/25 at 60 mL/min; Column Temp: 38° C.: Nozzle Pressure: 100Bar; Nozzle Temp: 60° C.: Evaporator Temp: 20° C.; Trimmer Temp: 25° C.:Wavelength: 220 nm) to yield(R)-5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroiso-quinolin-6-yl)hexanoicacid, and(S)-5-(2-(4-cyano-3-methyl-1-(p-tolyl)-H-pyrazol-5-yl)-1,2,3,4-tetra-hydro-isoquinolin-6-yl)hexanoicacid. ¹H NMR (400 MHz, CDCl₃) δ (400 MHz, ppm): 7.43 (d, J=8.2 Hz, 2H),7.21 (d, J=8.2 Hz, 2H), 7.00-6.91 (m, 2H), 6.88 (s, 1H), 4.43 (s, 2H),3.34 (t, J=5.7 Hz, 2H), 2.74 (t, J=5.3 Hz, 2H), 2.68-2.57 (m, 1H), 2.37(s, 3H), 2.34 (s, 3H), 2.32-2.25 (m, 2H), 1.64-1.42 (m, 4H), 1.20 (d,J=7.0 Hz, 3H). ESI MS m/z 443.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ (400MHz, ppm): 7.44 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 6.99-6.92 (m,2H), 6.88 (s, 1H), 4.43 (s, 2H), 3.35 (t, J=5.7 Hz, 2H), 2.74 (t, J=5.3Hz, 2H), 2.68-2.56 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 2.32-2.26 (m,2H), 1.66-1.42 (m, 4H), 1.21 (d, J=7.0 Hz, 3H). ESI MS m/z 443.1 [M+H]⁺.

Example 1295-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile

Step A.5-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile.To a solution of 5-bromo-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile(Intermediate 11, 600 mg, 2.173 mmol) in DMSO (20 ml) was added6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (434 mg, 2.173mmol), Cs₂CO₃ (1416 mg, 4.35 mmol) and CuI (414 mg, 2.173 mmol). Themixture was stirred at 140° C. for 18 h. The mixture was diluted withwater (2×20 mL) and extracted with EtOAc (2×50 mL). The combined organiclayers were dried over Na₂SO₄. filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE:EtOAc=50:1to 30:1) to yield the title compound.

Step B.5-(6-hydroxy-3,4-dihydroisoquinolin-2(H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile.To a solution of5-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile(180 mg, 0.502 mmol) in DCM (20 ml) was added BBr₃ (252 mg, 1.004 mmol)dropwise at −76° C. The mixture was stirred at −76° C. for 2 h. Themixture was diluted with water and extracted with EtOAc (2×30 mL). Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedin vacuo. The residue was purified by reverse phase HPLC on a GILSON 281instrument fitted with a Phenomenex Synergi C18 (250×21.2 mm×4 μm) usingwater (0.2% Formic acid) and CH₃CN as eluents (Mobile phase A: water(0.2% Formic acid), Mobile phase B: CH₃CN, Detective wavelength: 220 nm)followed by concentration (below 50° C.) to obtain the title compound.¹H NMR (CDCl₃, 400 MHz. ppm): δ 7.45 (d, J=8.22 Hz, 2H) 7.23 (d, J=8.22Hz, 2H) 6.90 (d, J=8.61 Hz, 1H) 6.65 (d, J=8.22 Hz, 1H) 6.58 (s, 1H)4.40 (s, 2H) 3.30-3.41 (m, 2H) 2.74 (t, J=5.48 Hz, 2H) 2.31-2.44 (m 6H).ESI MS m/z 345.1 [M+H]⁺.

Example 1305-(6-(2-hydroxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile

Step A.5-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile.To a solution of (2-bromoethoxy)tert-butyl) dimethylsilane (34 mg, 0.142mmol) in MeCN (20 mL) was added Cs₂CO₃ (114 mg, 0.348 mmol) and themixture was stirred at 15° C. for 30 min. Then5-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile(40 mg, 0.116 mmol) was added and the mixture was stirred at 15° C. for24 h. The mixture was washed with water (2×10 mL) and extracted withEtOAc (2×30 mL). The extract was dried over by Na₂SO₄ and concentratedin vacuo to give the crude title compound.

Step B.5-(6-(2-hydroxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrileTo a stirred solution of5-(6-(2-((tert-butyldimethyl-silyl)oxy)-ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile(50 mg, 0.099 mmol) in THF (20 mL) was added TBAF (0.199 mL, 0.199 mmol)in THF (1 M), and the mixture was stirred at 15° C. for 4 h. The mixturewas washed with water (2×10 mL) and extracted with EtOAc (2×30 mL). Theextract was dried over by Na₂SO₄ and evaporated in vacuo. The residuewas purified by reverse phase HPLC on a GILSON 281 instrument fittedwith a Phenomenex Synergi C18 (250×21.2 mm×4 μm) using water (0.2%Formic acid) and CH₃CN as eluents (Mobile phase A: water (0.2% Formicacid). Mobile phase B: CH₃CN, Detector wavelength: 220 nm) followed byconcentration to obtain the title compound. ¹H-NMR (400 MHz, CDCl₃) δppm: 7.46 (d, J=8.28 Hz, 2H) 7.23 (d, J=8.28 Hz, 2H) 6.96 (d, J=8.53 Hz,1H) 6.76 (dd, J=8.41, 2.38 Hz, 1H) 6.67 (s, 1H) 4.41 (s, 2H) 4.03-4.10(m, 2H) 3.91-4.00 (m, 2H) 3.37 (t, J=5.77 Hz, 2H) 2.77 (t, J=5.77 Hz,2H) 2.39 (s, 3H) 2.36 (s, 3H). m/z 389.1 [M+H]⁺.

Example 1313-(2-(5-cyclobutoxy-2,3-difluorophenyl)-7-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid

Step A. ethyl3-(2-(5-cyclobutoxy-2,3-difluorophenyl)-7-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoate.To a solution of 5-cyclobutoxy-2,3-difluorophenyltrifluoromethanesulfonate (50 mg, 0.150 mmol) in 1,4-dioxane (5 ml) wasadded ethyl 3-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(Intermediate 49, 38 mg, 0.151 mmol), Cs₂CO₃ (147 mg, 0.451 mmol),t-buxphos (7 mg, 0.016 mmol) and Pd₂(dba)₃ (14 mg. 0.015 mmol). Then thereaction mixture was placed under nitrogen and stirred at 90° C. for 16h. The mixture was concentrated in vacuo, and water (10 mL) was added tothe residue. The mixture was extracted with EtOAc (2×20 mL), and thecombined organic layers were concentrated in vacuo. The crude productwas purified by silica gel preparative TLC (PE/EtOAc=5:1) to give thetitle compound.

Step B.3-(2-(5-cyclobutoxy-2,3-difluorophenyl)-7-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid. To a solution of ethyl3-(2-(5-cyclobutoxy-2,3-difluorophenyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(20 mg, 0.046 mmol) in THF (2 ml), MeOH (2 ml) and water (1 ml) wasadded LiOH hydrate (4 mg, 0.095 mmol). The mixture was stirred at 15° C.for 3 h, then acidified with HCl (6 N), and extracted with EtOAc (2×20mL). The organic layer was washed with water (20 mL), dried overanhydrous Na₂SO₃, and concentrated in vacuo to give the crude product.The crude product was purified with a Phenomenex Synergi C18 (250×21.2mm×4 μm) using water (0.2% Formic acid) and CH₃CN as eluents (Mobilephase A: water (0.2% Formic acid), Mobile phase B: CH₃CN, Detectivewavelength: 220 nm) followed by concentration to obtain title compound.¹H NMR (400 MHz, CDCl₃) δ ppm 1.61-1.73 (m, 2H) 2.13 (dd, J=19.96, 9.78Hz, 2H) 2.39 (br. s., 2H) 2.64-2.72 (m, 2H) 2.90 (d, J=5.09 Hz, 2H)2.92-2.98 (m, 2H) 3.42 (t, J=5.67 Hz, 2H) 4.22 (s, 2H) 4.51 (t, J=7.04Hz, 1H) 6.20 (d, J=6.26 Hz, 2H) 6.77 (d, J=10.17 Hz, 1H) 6.98 (d, J=7.43Hz, 1H). m/z 406.1 [M+H]⁺.

Example 1326-(2-(1H-tetrazol-5-yl)ethyl)-2-(2,3-difluoro-5-((1r,3r)-3-methoxylcyclobutoxy)-phenyl)-1,2,3,4-tetrahydroisoquinoline

Step A. Tert-butyl6-(3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. To astirred solution of ethyl3-(1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoate (Intermediate 7, 2.0g, 8.57 mmol) in DCM (15 mL) were added (BOC)₂O (2.7 g, 12.37 mmol) andEt₃N (4.0 mL, 28.7 mmol) at rt. Then the reaction mixture was stirred atrt for 5 h. The solvent was removed under reduced pressure, and theresulting crude product was purified by silica gel column chromatography(PE:EtOAc=2:1) to give the title compound.

Step B.3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid: To a stirred solution of tert-butyl6-(3-ethoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.84g, 8.52 mmol) in THF (6 mL), MeOH (3 mL) and water (2.5 mL) was addedLiOH hydrate (1.7 g, 40.5 mmol) at rt (˜8° C.). Then the reactionmixture was stirred at rt (˜8° C.) for 15 h. The mixture was acidifiedto pH˜2 with HCl (15 mL, 3 N, a.q.) and extracted with EtOAc (20 mL×2).The organic layer was removed under reduced pressure to give the crudetitle compound.

Step C. Tert-butyl6-(3-amino-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. To astirred solution of3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid (2.46 g, 8.06 mmol) in DMF (10 mL) were added ammonium chloride(480 mg, 8.97 mmol), DIEA (4.2 mL, 24.05 mmol) and HATU (3.06 g, 8.06mmol) at rt. Then the reaction mixture was stirred at rt for 15 h. Themixture was diluted with water (200 mL), extracted with EtOAc (30 mL×2),and the organic layer was concentrated in vacuo to give the titlecompound.

Step D. 3-(1,2,3,4-tetrahydroisoquinolin-6-yl)propanenitrile. A solutionof tert-butyl6-(3-amino-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.4g, 7.88 mmol) in phosphorus oxychloride (28.93 g, 189 mmol) was stirredat rt for 5 h. The mixture was poured into water (300 mL) slowly withstirring, then basified to pH˜8 with saturated aqueous of NaHCO₃ (200mL), extracted with DCM/MeOH (10:1, 50 mL×2). The organic layer wasconcentrated in vacuo. The resulting crude product was purified bysilica gel column chromatography (DCM to DCM/MeOH=40:1 to 10:1) to givethe title compound.

Step E.3-(2-(2,3-difluoro-5-((1r,3r)-3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanenitrile.To a solution of 3-(1,2,3,4-tetrahydro-isoquinolin-6-yl)propanenitrile(100 mg, 0.537 mmol) in toluene (10 mL) were added2,3-difluoro-5-((1R,3R)-3-methoxycyclobutoxy)phenyltrifluoromethanesulfonate (Intermediate 4, 204 mg, 0.564 mmol), Cs₂CO₃(525 mg, 1.611 mmol), BINAP (67 mg, 0.108 mmol) and Pd(OAc)₂ (12 mg,0.053 mmol) at rt. Then the reaction mixture was placed under nitrogenatmosphere and stirred at 110° C. for 15 h. The solvent was removed invacuo, and the resulting mixture was diluted with water (20 mL) andextracted with EtOAc (20 mL×2). The organic layer was concentrated invacuo, and the crude product was purified by silica gel PTLC(PE/EtOAc=2:1) to give the title compound. m z 399.1 [M+H]⁺.

Step F6-(2-(1H-tetrazol-5-yl)ethyl)-2-(2,3-difluoro-5-((R,3R)-3-methoxy-cyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline:To a solution of3-(2-(2,3-difluoro-5-((R,3R)-3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propanenitrile (50 mg, 0.125 mmol) in toluene (4 mL) was added azidotributyltin(0.2 mL, 0.730 mmol) at rt. Then the reaction mixture was placed under anitrogen atmosphere and stirred at 110° C. for 40 h. The solvent wasremoved in vacuo, and the resulting mixture was diluted with water (10mL), and extracted with EtOAc (10 mL×2). The organic layer wasconcentrated in vacuo, and the crude product was purified by silica gelcolumn chromatography (DCM to DCM/MeOH=20:1), then purified by reversephase HPLC on a GILSON 281 instrument fitted with a Phenomenex SynergiC18 (250×21.2 mm×4 μm) using water (0.2% Formic acid) and CH₃CN aseluents (Mobile phase A: water (0.2% Formic acid), Mobile phase B:CH₃CN, Detective wavelength: 220 nm) followed by concentration to givethe title compound. ¹H NMR (400 MHz, MeOD) δ 7.03-7.08 (m, 1H),6.94-7.00 (m, 2H), 6.23-6.32 (m, 2H), 4.66-4.76 (m, 1H), 4.04-4.13 (m,1H), 3.42 (t, J=5.73 Hz, 2H), 3.19-3.27 (m, 5H), 3.02-3.09 (m, 2H), 2.88(t, J=5.51 Hz, 2H), 2.27-2.41 (m, 4H). m/z 440.2 [M−H]⁺.

The examples in Table 5 were prepared from the appropriate startingmaterials described previously or commercially available startingmaterials available using procedures described in Examples 127-132.

TABLE 5 Example Structure Name [M + H]⁺ 133

5-{2-[4-cyano-1-(4- methoxyphenyl)-3-methyl- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl} pentanoic acid 445.1 134

5-{2-[4-cyano-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}pentanoic acid 429.1 135

5-{2-[2-fluoro- 5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}pentanoic acid 412.1 136

5-[6-(2-hydroxyethoxy)- 3,4-dihydroisoquinolin- 2(1H)-yl]-3-methyl-1-(4-methylphenyl)- 1H-pyrazole-4-carbonitrile 389.1 137

5-{2-[4-chloro-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}pentanoic acid 438.2 138

5-(6-hydroxy-3,4- dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(4-methylphenyl)- 1H-pyrazole-4-carbonitrile 345.1 139

5-[6-(4-hydroxybutoxy)-3,4- dihydroisoquinolin-2(1H)-yl]-3-methyl-1-(4-methylphenyl)- 1H-pyrazole-4-carbonitrile 417.2 140

5-{2-[4-cyano-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}hexanoic acid 443.1 141

5-(3,4-dihydroisoquinolin- 2(1H)-yl)-1- (4-methoxyphenyl)-3-methyl-1H-pyrazole- 4-carbonitrile 345.1 142

5-{2-[4-cyano-3-methyl- 1-(4-methylphenyl)- 1H-pyrazol-5-yl]-1,2,3,4-tetrahydroisoquinolin- 6-yl}hexanoic acid 443.1 143

3-(2-{[4-fluoro-3-methyl- 1-(4-methylphenyl)-1H-pyrazol-5-yl]methyl}-1,2,3,4- tetrahydroisoquinolin- 6-yl)propanoicacid408.2 144

5-[6-(3-hydroxypropoxy)- 3,4-dihydroisoquinolin- 2(1H)-yl]-3-methyl-1-(4-methylphenyl)- 1H-pyrazole-4-carbonitrile 403.1 145

3-{2-[5-(cyclobutyloxy)- 2,3-difluorophenyl]- 1-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 406.1 146

3-{2-[4-chloro-3-methyl- 1-(4-methylphenyl)-1H-pyrazol-5-yl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl}propanoicacid 428.1

Example 1473-[2-(3-Cyano-4-methyl-6-thiazol-4-yl-pyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl]-propionicacid

Step A Ethyl3-(2-(6-chloro-3-cyano-4-methylpyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate. To a solution of2,6-dichloro-4-methylnicotinonitrile (200 mg, 1.069 mmol), ethyl3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (269 mg, 1.069mmol) and G2-RuPHOS (41.5 mg, 0.053 mmol) in dioxane (6 ml) was addedCs₂CO₃ (697 mg, 2.139 mmol). The mixture was stirred at 90° C. for 12 h,and then water (15 ml) was added, and the mixture was extracted with EA(10 mL×2). The organic layer was separated, washed with brine (15 ml).and dried over Na₂SO₄. After filtration and concentration, the resultingresidue was purified by prep-TLC (SiO₂, PE:EA=5:1) to afford the titlecompound.

Step B: Ethyl3-(2-(3-cyano-4-methyl-6-(thiazol-4-yl)pyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of ethyl3-(2-(6-chloro-3-cyano-4-methylpyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(50 mg, 0.124 mmol) and 4-(tributylstannyl)thiazole (51.2 mg, 0.137mmol) in dioxane (3 ml) was added G2 XPhos (9.79 mg, 0.012 mmol). Themixture was stirred at 110° C. for 12 h, then quenched with 10% aqueousKF (10 ml). filtered and extracted with ethyl acetate (8 mL×3). Theorganic layers were combined and washed with water (15 mL), brine (10mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the title compound, which was used directly without furtherpurification.

Step C:3-[2-(3-Cyano-4-methyl-6-thiazol-4-yl-pyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl]-propionicacid. To a solution of ethyl3-(2-(3-cyano-4-methyl-6-(thiazol-4-yl)pyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(50 mg, 0.111 mmol) in MeOH (2 ml), THF (2 ml) and water (1 ml) wasadded lithium hydroxide hydrate (46.6 mg, 1.110 mmol). The mixture wasstirred at 85° C. for 5 h. The resulting mixture was acidified by HCl (1N) to pH=6-7, then extracted with ethyl acetate (2×15 mL). The combinedorganic layers were washed with brine (20 mL), dried (Na₂SO₄), filteredand the solvent was evaporated under reduced pressure. The resultingresidue was purified by prep-HPLC (TFA) to afford the title compound.¹H-NMR (400 MHz, METHANOL-d): 9.07 (d, J=1.98 Hz, 1H), 8.37 (d, J=1.98Hz, 1H), 7.60 (s, 1H), 7.09-7.16 (m, 1H), 6.99 (d, J=7.94 Hz, 1H), 4.84(s, 2H), 4.00 (t, J=5.73 Hz, 2H), 3.04 (t, J=5.51 Hz, 2H), 2.93 (t,J=7.61 Hz, 2H), 2.59 (t. J=7.61 Hz, 2H), 2.55 (s, 3H).

Example 1483-(2-(6-cyclobutoxy-3-fluoro-4-methoxypyridin-2-yl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid

Step A Ethyl3-(2-(6-cyclobutoxy-3-fluoro-4-methoxypyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.To a solution of 2-bromo-6-cyclobutoxy-3-fluoro-4-methoxypyridine (150mg, 0.545 mmol) and ethyl3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl) propanoate (123 mg,0.49 mmol) in dioxane (5 ml) was added Cs₂CO₃ (354 mg, 1.09 mmol), andthen G2 Ruphos (28 mg, 0.03 mmol) was added under N₂ protection. Theresultant mixture was stirred at 90° C. for 10 h, then quenched with H₂O(10 mL) and extracted with EA (20 mL×3). The organic layer was washedwith brine (30 mL). dried over Na₂SO₄, filtered and the filtrate wasevaporated under reduced pressure to afford the title compound, whichwas used in the next step without further purification. MS (ESI) m/z:447 [M+H⁺].

Step B3-(2-(6-cyclobutoxy-3-fluoro-4-methoxypyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid. To a solution of ethyl3-(2-(6-cyclobutoxy-3-fluoro-4-methoxypyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (76 mg, 0.17 mmol) in MeOH (2.5 ml) and H₂O (0.5 ml) wasadded lithium hydroxide (20 mg, 0.85 mmol), and the resulting mixturewas stirred at 18-25° C. for 6 hours. Then the reaction mixture wasextracted with EA (10 mL 3). The organic layer was washed with brine (20mL), and dried over Na₂SO₄. After filtration and concentration, theresulting residue was purified by preparative HPLC (TFA) to afford thetitle compound. ¹H-NMR (400 MHz, METHANOL-d4) 7.06 (t, J=7.63 Hz, 1H),6.88 (d, J=7.83 Hz, 1H), 5.90 (d, J=3.91 Hz, 1H), 4.93-5.04 (m, 1H),4.54 (s, 2H), 3.82 (s, 3H), 3.71 (t, J=5.87 Hz, 2H), 2.88 (t, J=7.63 Hz,2H), 2.82 (t, J=5.48 Hz, 2H), 2.55 (t, J=7.63 Hz, 2H), 2.26-2.44 (m,2H), 1.92-2.12 (m, 2H), 1.78 (q, J=9.91 Hz, 1H), 1.53-1.71 (m, 1H). MS(ESI) m/z: 419 [M+H⁺]

Example 1493-(2-(3-cyano-6-cyclobutoxy-2-methylpyridin-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid

Step A 6-chloro-2-methylpyridin-3-amine. A mixture of6-chloro-2-methyl-3-nitropyridine (8.60 g, 50.00 mmol), NH₄Cl (27.00 g,500.00 mmol) and Fe (14.00 g, 250.00 mmol) in MeOH (100 mL) was stirredat 80° C. for 5 h. The mixture was filtered and concentrated, and theresulting residue was purified by column chromatography (SiO₂, elutingwith PE:EA=5:1) to afford the title compound.

Step B 4-bromo-6-chloro-2-methylpyridin-3-amine. To a solution of6-chloro-2-methyl-pyridin-3-amine (4.97, 35.00 mmol) in CH₃CN (100 mL)was added NBS (6.23 g, 35.00 mmol) at 0° C. The resulting mixture wasstirred at 26° C. for 16 h, then quenched with H₂O and extracted withEtOAc (3*100 mL). The combined organic layers were washed with brine(200 mL), and dried over Na₂SO₄. After filtration and concentration, theresulting residue was purified by column chromatography (SiO₂, elutingwith PE:EA=5:1) to afford the title compound. ¹H-NMR (400 MHz,chloroform-d): 7.28 (s, 1H), 4.06 (br. 2H), 2.43 (s, 3H).

Step C: 4-bromo-6-chloro-2-methylnicotinonitrile. To a solution of CuCN(1.80 g, 20.09 mmol) in CH₃CN (20 mL) was added 3-methyl-1-nitrobutane(2.80 mL, 20.93 mmol). Then a solution of4-bromo-6-chloro-2-methylpyridin-3-amine (3.70 g, 16.74 mmol) in CH₃CN(30 mL) was added to the mixture dropwise. The resulting reactionmixture was stirred at 65° C. for 16 h, then quenched with H₂O andextracted with EtOAc (3*50 mL). The combined organic layers were washedwith brine (100 mL), and dried over Na₂SO₄. After filtration andconcentration, the resulting residue was purified by columnchromatography (SiO₂, eluting with PE:EA=10:1) to afford the titlecompound.

Step D 4-bromo-6-cyclobutoxy-2-methylnicotinonitrile. A solution of NaH(40.00 mg, 1.00 mmol) and cyclobutanol (72.00 mg, 1.00 mmol) in THF (3mL) was cooled to −78° C. under N₂ protection. The solution was stirredat −78° C. for 30 min, and then4-bromo-6-chloro-2-methyl-nicotinonitrile (230.00 mg, 1.00 mmol) wasadded. The resulting reaction mixture was stirred at 26° C. for 16 h,then quenched with H₂O and extracted with EtOAc (3*20 mL). The combinedorganic layers were washed with brine (50 mL), and dried over Na₂SO₄.After filtration and concentration, the residue was purified by columnchromatography (SiO₂, eluting with PE:EA=10:1) to afford the titlecompound. ¹H-NMR (400 MHz, chloroform-d): 6.84 (s, 1H), 5.21-5.15 (m,1H), 2.66 (s, 3H), 2.47-2.41 (m, 2H), 2.18-2.08 (m, 2H), 1.89-1.84 (m,1H), 1.69-1.64 (m, 1H).

Step E Ethyl3-(2-(3-cyano-6-cyclobutoxy-2-methylpyridin-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate.A mixture of 4-bromo-6-cyclobutoxy-2-methyl-nicotinonitrile (40.00 mg,0.15 mmol), ethyl 3-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate (45.00 mg, 0.18 mmol), Cs₂CO₃ (147.00 mg, 0.45 mmol) andG2-Ruphos (6.00 mg, 0.0075 mmol) in 1,4-dioxane (5 mL) was stirred at90° C. under N₂ for 16 h. Then the reaction was diluted with H₂O andextracted with EtOAc (10 mL*3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to afford the title compound,which was used in the next step without further purification. MS(ESI)m/z: 438.7 [M+H]+

Step F3-(2-(3-cyano-6-cyclobutoxy-2-methylpyridin-4-yl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid. A mixture ofethyl-3-(2-(3-cyano-6-cyclobutoxy-2-methyl-pyridin-4-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate(65.00 mg, 0.15 mmol) and LiOH H₂O (126.00 mg, 3.00 mmol) in MeOH (5 mL)and H₂O (1 mL) was stirred at 26° C. for 17 h. Then the reactionsolution was adjusted with 3 N HCl to pH=7, and the reaction solutionwas extracted with EtOAc (20 mL*3). The combined organic layers weredried over Na₂SO₄. After filtration and concentration, the resultingresidue was purified by prep-HPLC (Neutral) to afford the titlecompound. 1H-NMR (400 MHz, chloroform-d) 7.14-7.10 (m, 1H), 6.94 (d,J=7.8 Hz, 1H), 6.15 (s, 1H), 5.14 (t, J=7.4 Hz, 1H), 4.51 (s, 2H), 3.80(t, J=5.7 Hz, 2H), 2.99-2.89 (m, 4H), 2.59-2.54 (m, 5H), 2.45-2.43 (m,2H), 2.14-2.09 (m, 2H), 1.85-1.68 (m, 2H). MS(ESI) m/z: 410.7 [M+H]⁺

The Examples in Table 6 were prepared from the appropriate startingmaterials described previously or commercially available startingmaterials using procedures similar to those in the Examples above.

TABLE 6 Example Structure Name [M + H]+ 150

3-{2-[3-chloro-2-cyano- 5-(cyclobutyloxy)phenyl]- 5-fluoro-1,2,3,4-tetrahydroisoquinolin- 6-yl}propanoic acid 429.2 151

3-{2-[5-cyano-4- (cyclobutyloxy)-6- methylpyrimidin-2-yl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl}propanoic acid 411   152

3-{2-[5-cyano-2- (cyclobutyloxy)-6- methylpyrimidin-4-yl]-5-fluoro-1,2,3,4- tetrahydroisoquinolin- 6-yl}propanoic acid 411   153

3-{5-chloro-2-[2-cyano- 5-(cyclobutyloxy)-3- fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}- propanoic acid 429   154

3-[2-(6-cyclopropylpyridin- 2-yl)-5-fluoro-1,2,3,4- tetrahydroiso-quinolin-6-yl] propanoic acid 341.2 155

3-{2-[2-cyano- 5-(cyclobutyloxy)-3- fluorophenyl]-5- fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}- propanoic acid 413.3 156

3-{2-[2,3-dichloro- 5-(trifluoromethoxy) phenyl]-1,2,3,4-tetra-hydroisoquinolin- 6-yl}propanoic acid 434   157

3-{2-[2-cyano- 5-(cyclobutyloxy)- 3-fluorophenyl]- 5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl}- propanoic acid 409  

Biological Assays

The usefulness of the compound encompassed by formula (I) for amedicament is shown in tests described below.

Human GPR120 IP1 Assay Principle

The binding of small molecule agonists to the G-protein-coupled receptorGPR120 activates phospholipase C, and leads to the generation ofinositol 1,4,5-trisphosphate (InsP3 or IP3). IP3 is subsequentlyde-phosphorylated to IP1, which accumulates in cells and is stable inthe presence of lithium chloride.

In the present method, agonist-induced activation of the human GPR120receptor was monitored by measuring the accumulation of IP1 in CHO-K1cells that were stably expressing the short form of human GPR120(Accession #NM_001195755). Following agonist addition, GPR120 activationand subsequent accumulation of IP1 was measured using a homogeneous TimeResolved Fluorescence-based ELISA commercially available from CisBio(IP-one ELISA Kit). The IP-One ELISA was a competitive immunoassay whichuses IP1 labeled with HRP and a terbium cryptate-labeled anti-IP1monoclonal antibody. Accumulation of unlabeled IP1 following GPR120activation resulted in a loss of signal in the ELISA. The signal losswas then back calculated to IP1 concentration using an IP1 standardcurve. Determination of IP1 concentration was a direct measure of GPR120activation and was used to determine compound potency (EC50).

Generation of GPR120-Expressing Cells:

Human GPR120 stable cell-lines were generated in CHO cells. Theexpression plasmids were transfected using lipofectamine (LifeTechnologies) following manufacturer's instructions. Stable cell-lineswere generated following drug selection and single cell cloning.

Inositol Phosphate Turnover (IP1) Assay:

The assay was performed in 384-well format. CHO cells stably expressinghuman GPR120 were plated at 20.00 cells per well in growth medium(DMEM/F12, 10% fetal calf serum). Cell plates were then incubated 16hours at 37 degrees in a 5% CO₂ incubator. Measurement of InositolPhosphate Turnover (IP1) was performed using the CisBio IP-One kit (Partnumber 62IPAPEB). After the 16 hour incubation, the growth media wasremoved by centrifugation using the BlueWasher (AusWasher GUI Ver.v1.0.1.8) Protocol #21-“Light Dry” and 10 ul of stimulation buffer(prepared as described in the kit) was added to each well. In a separateplate, compounds were diluted in DMSO (200-fold over the finalconcentration in the assay well) and 50 nl was acoustically transferredto the appropriate well in the assay cell plate. The plates were thenincubated for 60 minutes at 37 degrees in a 5% CO₂ incubator. 10 ul ofdetection buffer (also prepared as described in the IP-One kit) wasadded to each well and the plates were incubated at room temperature for60 minutes in the dark. The plates were then read in a Perkin ElmerEnVision or equivalent reader able to measure FRET. Fluorescent ratio ofemission at 665 and 620 nm was then converted to the IP1 concentrationby back calculating from an IP1 standard curve prepared at the time ofthe assay. The data was normalized to % activity using a referencecompound, and the EC₅₀ values were determined using a standard4-parameter fit.

The compounds of the present invention, including the compounds inExamples 1-157, have EC₅₀ values ≤10,000 nanomolar (nM) in the HumanGPR120 IP1 Assay described above. Specific EC₅₀ values in the HumanGPR120 IP1 Assay are provided in Table I.

TABLE I Specific EC₅₀ values in the Human GPR120 IP1 Assay hGPR120Example EC₅₀ 1 61 2 17 3 29 4 51 5 65 6 417 7 533 8 414 9 20 10 14 11 1512 24 13 18 14 20 15 22 16 22 17 23 18 24 19 27 20 29 21 51 22 56 23 6024 61 25 65 26 97 27 61 28 169 29 171 30 134 31 182 32 233 33 192 34 18435 312 36 348 37 377 38 405 39 417 40 463 41 569 42 798 43 1466 44 236545 2291 46 5392 47 91 48 596 49 223 50 348 51 317 52 510 53 533 54 168355 25 56 40 57 Isomer 1: 58; Isomer 2: 231 58 472 59 1634 60 60 61 28 623 63 14 64 15 65 37 66 41 67 40 68 58 69 231 70 472 71 309 72 1174 731634 74 60 75 358 76 845 77 5880 78 19 79 471 80 3123 81 48 82 25 83 10084 118 85 40 86 61 87 74 88 110 89 185 90 250 91 59 92 482 93 350 94 47395 491 96 834 97 1581 98 100 99 127 100 251 101 273 102 118 103 2999 1044036 105 6606 106 83 107 122 108 122 109 22 110 42 111 32 112 42 113 59114 61 115 83 116 107 117 143 118 215 119 273 120 299 121 73 122 121 123766 124 824 125 414 126 9742 127 35 128 Isomer 1: 312; Isomer 2: 209 12992 130 87 131 174 132 406 133 50 134 41 135 77 136 87 137 93 138 92 139187 140 209 141 288 142 312 143 395 144 4300 145 174 146 309 147 141 1489 149 33 150 16 151 34 152 69 153 87 154 167 155 17 156 62 157 15

Example of a Pharmaceutical Formulation

As a specific embodiment of an oral composition of a compound of thepresent invention, 50 mg of any of the examples is formulated withsufficient finely divided lactose to provide a total amount of 580 to590 mg to fill a size O hard gelatin capsule. While the invention hasbeen described and illustrated in reference to specific embodimentsthereof, various changes, modifications, and substitutions can be madetherein without departing from the invention. For example, alternativeeffective dosages may be applicable, based upon the responsiveness ofthe patient being treated. Likewise, the pharmacologic response may varydepending upon the particular active compound selected, formulation andmode of administration. All such variations are included within thepresent invention.

1. A compound according to the formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is (1) bond,(2) (C₁₋₂)alkyl, or (3) halo(C₁₋₂)alkyl; ring A is (1) aryl, (2) 5- or6-membered heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O and S, or (3) 9- or 10-membered fused heteroarylcontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; R¹ is (1) bond, (2) (C₁₋₆)alkyl, (3) —O—(C₁₋₆)alkyl-, or (4)(C₃₋₆)cycloalkyl; R² is (1) hydrogen, (2) hydroxy, (3) COOH, (4)tetrazole, (5) hydroxyisoxazole, (6) triazole, (7) C(O)NH₂, (8)C(O)NHC₁₋₆alkyl, (9) C(O)NHC₃₋₆cycloalkyl, (10)C(O)NHC₂₋₅cycloheteroalkyl, (11) C(O)NH-aryl, (12) C(O)NH-heteroaryl,(13) SO₂C₁₋₆alkyl, (14) SO₂C₃₋₆cycloalkyl, (15) SO₂C₂₋₅cycloheteroalkyl,(16) SO₂-aryl, or (17) SO₂-heteroaryl; R³ is (1) hydrogen, (2) halogen,(3) cyano, or (4) (C₁₋₃)alkyl; R⁴ is (1) hydrogen, (2) (C₁₋₃)alkyl, (3)halo(C₁₋₃)alkyl, or (4) halogen; R⁵ is (1) cyano, (2) (C₁₋₃)alkyl, (3)halo(C₁₋₃)alkyl, (4) (C₁₋₃)alkoxy, (5) halo(C₁₋₃)alkoxy, or (6) halogen;R⁶ is (1) (C₁₋₃)alkoxy, (2) halo(C₁₋₃)alkoxy, (3) halo(C₁₋₃)alkyl, (4)(C₃₋₆)cycloalkyl, (5) (C₃₋₆)cycloalkyl-O—, (6) (C₃₋₆)cycloalkyl-S—, (7)(C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-, (8) (C₃₋₆)cycloalkyl-halo(C₁₋₂)alkyl-,(9) phenyl, (10) 5- to 6-membered heteroaryl-O— wherein the heteroarylcontains 1, 2, or 3 heteroatoms independently selected from N, O and S,or (11) 5- to 6-membered heteroaryl- wherein the heteroaryl contains 1,2, or 3 heteroatoms independently selected from N, O and S, whereinalkyl, cycloalkyl, phenyl and heteroaryl are unsubstituted orsubstituted with 1-3 substituents selected from (C₁₋₃)alkyl,halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, and halogen; n is 0, 1,2 or 3; m is 0 or 1; p is 0, 1, 2 or 3; and q is 0, 1, or
 2. 2. Thecompound of claim 1 wherein X is (1) bond, or (2) (C₁₋₂)alkyl; or apharmaceutically acceptable salt thereof.
 3. The compound of claim 1wherein X is a bond; or a pharmaceutically acceptable salt thereof. 4.The compound of claim 1 wherein ring A is phenyl, pyridine, pyrimidine,pyrazole, pyrazine, isothiaozole, or benzisoxazole; or apharmaceutically acceptable salt thereof.
 5. The compound of claim 1wherein R² is (1) hydrogen, (2) hydroxy, (3) COOH, or (4) tetrazole; ora pharmaceutically acceptable salt thereof.
 6. The compound of claim 1wherein R² is COOH; or a pharmaceutically acceptable salt thereof. 7.The compound of claim 1 wherein R³ is (1) hydrogen, (2) halogen, or (3)(C₁₋₃)alkyl; or a pharmaceutically acceptable salt thereof.
 8. Thecompound of claim 1 wherein R³ is (1) hydrogen, or (2) halogen; or apharmaceutically acceptable salt thereof.
 9. The compound of claim 1wherein R⁴ is (1) hydrogen, or (2) (C₁₋₃)alkyl; or a pharmaceuticallyacceptable salt thereof.
 10. compound of claim 1 wherein R⁴ is hydrogen;or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1 wherein R⁵ is (1) cyano, (2) (C₁₋₃)alkyl, (3) halo(C₁₋₃)alkyl, (4)(C₁₋₃)alkoxy, or (5) halogen; or a pharmaceutically acceptable saltthereof.
 12. The compound of claim 1 wherein R⁵ is (1) cyano, or (2)halogen; or a pharmaceutically acceptable salt thereof.
 13. The compoundof claim 1 wherein R⁶ is (1) halo(C₁₋₃)alkoxy, (2) halo(C₁₋₃)alkyl, (3)(C₃₋₆)cycloalkyl, (4) (C₃₋₆)cycloalkyl-O—, (5) (C₃₋₆)cycloalkyl-S—, (6)(C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-, (7) phenyl, (8) 5- to 6-memberedheteroaryl-O— wherein the heteroaryl contains 1, 2, or 3 heteroatomsindependently selected from N, O and S, or (9) 5- to 6-memberedheteroaryl- wherein the heteroaryl contains 1, 2, or 3 heteroatomsindependently selected from N, O and S, wherein alkyl, cycloalkyl,phenyl and heteroaryl are unsubstituted or substituted with 1-3substituents selected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy,halo(C₁₋₃)alkoxy, and halogen; or a pharmaceutically acceptable saltthereof.
 14. The compound of claim 1 wherein R⁶ is (C₃₋₆)cycloalkyl-O—,wherein cycloalkyl is unsubstituted or substituted with 1-3 substituentsselected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy,halo(C₁₋₃)alkoxy, and halogen; or a pharmaceutically acceptable saltthereof.
 15. A compound according to the formula I:

wherein: X is (1) a bond, or (2) (C₁₋₂)alkyl; ring A is (1) aryl, (2) 5-or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O and S, or (3) 9- or 10-membered fused heteroarylcontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; R¹ is (1) bond, (2) (C₁₋₆)alkyl, (3) —O—(C₁₋₆)alkyl-, or (4)(C₃₋₆)cycloalkyl; R² is (1) hydrogen, (2) hydroxy, (3) COOH, or (4)tetrazole; R³ is (1) hydrogen, (2) halogen, or (3) (C₁₋₃)alkyl; R⁴ is(1) hydrogen, or (2) (C₁₋₃)alkyl; R⁵ is (1) cyano, (2) (C₁₋₃)alkyl, (3)halo(C₁₋₃)alkyl, (4) (C₁₋₃)alkoxy, or (5) halogen; R⁶ is (1)halo(C₁₋₃)alkoxy, (2) halo(C₁₋₃)alkyl, (3) (C₃₋₆)cycloalkyl, (4)(C₃₋₆)cycloalkyl-O—, (5) (C₃₋₆)cycloalkyl-S—, (6)(C₃₋₆)cycloalkyl-(C₁₋₂)alkyl-, (7) phenyl, (8) 5- to 6-memberedheteroaryl-O— wherein the heteroaryl contains 1, 2, or 3 heteroatomsindependently selected from N, O and S, or (9) 5- to 6-memberedheteroaryl- wherein the heteroaryl contains 1, 2, or 3 heteroatomsindependently selected from N, O and S, wherein alkyl, cycloalkyl,phenyl and heteroaryl are unsubstituted or substituted with 1-3substituents selected from (C₁₋₃)alkyl, halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy,halo(C₁₋₃)alkoxy, and halogen; or a pharmaceutically acceptable saltthereof.
 16. A compound according to the formula I:

wherein: X is a bond; ring A is aryl; R¹ is (C₁₋₆)alkyl; R² is COOH; R³is (1) hydrogen, or (2) halogen; R⁴ is hydrogen; R⁵ is (1) cyano, or (2)halogen; R⁶ is (C₃₋₆)cycloalkyl-O—, wherein cycloalkyl is unsubstitutedor substituted with 1-3 substituents selected from (C₁₋₃)alkyl,halo(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halo(C₁₋₃)alkoxy, and halogen; or apharmaceutically acceptable salt thereof.
 17. A compound of claim 1selected from the group consisting of: 1)3-(2-(2-chloro-5-cyclobutoxy-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquino-lin-6-yl)-propanoicacid; 2)3-(2-(3-(difluoromethyl)-2-fluoro-5-(pyridin-2-yloxy)phenyl)-1,2,3,4-tetra-hydro-isoquinolin-6-yl)propanoicacid; 3)3-(2-(2,3-difluoro-5-(3-methoxycyclobutoxy)phenyl)-1,2,3,4-tetrahydroiso-quinolin-6-yl)-propanoicacid; 4)3-(2-(2-fluoro-4-methoxy-5-((5-methylthiazol-2-yl)oxy)phenyl)-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 5)3-(2-(6-cyclobutoxy-3-fluoropyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid; 6)3-(2-(5-cyclobutoxy-2-fluorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid; 7)3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)butanoic acid; 8)3-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)-butanoicacid; 9)3-(2-{3-chloro-2-fluoro-5-[(5-methyl-1,3-thiazol-2-yl)oxy]phenyl}-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid; 10)3-{2-[5-(cyclobutyloxy)-3-(difluoromethyl)-2-fluorophenyl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 11)3-{2-[5-(cyclobutyloxy)-2,3-difluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 12)3-{2-[3-cyano-5-(cyclobutyloxy)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 13)3-{2-[2-fluoro-3-methoxy-5-(trfluoromethoxy)phenyl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 14)3-(2-{3-(difluoromethyl)-2-fluoro-5-[(5-methyl-1,3-thiazol-2-yl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid; 15)3-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 16)3-(2-{3-(difluoromethyl)-2-fluoro-5-[(5-methylpyridin-2-yl)oxy]phenyl}-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 17)3-(2-{2-fluoro-3-methoxy-5-[(5-methyl-1,3-thiazol-2-yl)oxy]phenyl}-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 18)3-{2-[5-(cyclobutyloxy)-2-fluoro-3-methoxyphenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 19)3-{2-[5-(cyclobutyloxy)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 20)3-(2-{2,3-difluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid; 21)3-(2-{2-fluoro-4-methoxy-5-[(5-methyl-1,3-thiazol-2-yl)oxy]phenyl}-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 22)3-{2-[4-chloro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 23)3-{2-[5-(cyclobutylmethyl)-2-fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 24)3-{2-[2-chloro-5-(cyclobutyloxy)-4-methoxyphenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 25)3-{2-[6-(cyclobutyloxy)-3-fluoropyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 26)3-{2-[2-(cyclobutylsulfanyl)-5-fluoropyridin-4-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 27)3-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 28)3-(2-{2-fluoro-4-methoxy-5-[(5-methylpyridin-2-yl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid; 29)3-{2-[6-fluoro-3-(trifluoromethyl)-1,2-benzisoxazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 30)3-{7-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 31)3-{2-[5-(cyclobutyloxy)-2-fluoro-4-methoxyphenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 32)3-{2-[5-(cyclobutyloxy)-2,3-difluorophenyl]-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 33)3-{2-[2-fluoro-5-(pyrazin-2-yloxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 34)3-(2-{3-cyano-2-fluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydro-isoquinolin-6-yl)propanoicacid; 35)3-(2-{3-(difluoromethyl)-2-fluoro-5-[(5-fluoropyridin-2-yl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid; 36)3-{2-[5-(cyclobutyloxy)-2-fluorophenyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 37)3-{2-[2-chloro-5-(cyclobutyloxy)-3-fluorophenyl]-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 38)3-{2-[6-(cyclobutylsulfanyl)pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 39)3-{2-[5-(cyclobutyloxy)-2-fluorophenyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 40)3-{2-[3,5-dichloro-4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 41)3-{2-[6-(cyclobutyloxy)pyrazin-2-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 42)3-{2-[2-cyano-5-(cyclobutyloxy)-4-methoxyphenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}-propanoicacid; 43)3-{2-[4-cyano-1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydro-isoquinolin-6-yl}propanoicacid; 44)3-{2-[2-cyano-3-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 45)3-{2-[2-chloro-5-(cyclobutyloxy)-3-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 46)3-{2-[2-cyano-5-(cyclobutyloxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 47)3-{2-[4-fluoro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 48)3-{2-{2-cyano-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetra-hydroisoquinolin-6-yl}-propanoicacid; 49)3-{2-[5-(cyclobutyloxy)-2,3-difluorophenyl]-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl}-propanoicacid; 50)3-(2-{[3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methyl}-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 51)3-{8-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 52)3-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-2-methyl-propanoicacid; 53)3-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-butanoicacid; 54)3-{2-[3-chloro-5-(cyclobutyloxy)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 55)3-{2-[2-cyano-5-(cyclobutyloxy)-3-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 56)3-(2-(5-(cyclobutyldifluoromethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 57)3-(2-(3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)-2-methylpropanoicacid; 58)3-(5-fluoro-2-(2-fluoro-5-(trifluoromethoxy)phenyl)-7-methyl-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 59)3-(2-(3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)-5-fluoro-1,2,3,4-tetra-hydro-isoquinolin-6-yl)propanoicacid; 60)3-(2-(5-(cyclobutylmethyl)-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl)-propanoicacid; 61)3-(2-(5-cyclobutoxy-2-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-propanoicacid; 62)3-(2-{3-chloro-2-fluoro-5-[(5-methyl-1,3-thiazol-2-yl)oxy]phenyl}-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid; 63)3-{2-[6-(cyclobutyloxy)-3-fluoropyridin-2-yl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 64)3-{2-[5-(cyclobutyloxy)-2,3-difluorophenyl]-5-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 65)3-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 66)3-(2-{2,3-difluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl)propanoicacid; 67)3-(2-{5-[cyclobutyl(difluoro)methyl]-2-fluorophenyl}-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid; 68)3-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}-2-methylpropanoicacid; 69)3-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}-2-methylpropanoicacid; 70)3-{5-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-7-methyl-1,2,3,4-tetra-hydro-isoquinolin-6-yl}propanoicacid; 71)3-{2-[4-chloro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 72)3-{5-chloro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 73)3-{2-[3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 74)3-{2-[5-(cyclobutylmethyl)-2-fluorophenyl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 75)3-[2-(5-{[3-(difluoromethyl)cyclobutyl]oxy}-2,3-difluorophenyl)-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl]propanoicacid; 76)3-{2-[2-cyano-5-(cyclobutyloxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 77)3-{5-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}-2-methylpropanoicacid; 78)3-{2-[2-cyano-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 79)3-(2-(2-cyano-5-cyclobutoxy-3-fluorophenyl)-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2-methylpropanoicacid; 80)3-{5-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 81)3-{2-[5-(cyclobutyloxy)-2-fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 82)3-{2-[2-cyano-5-(cyclobutyloxy)-3-fluorophenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-propanoicacid; 83)(1S,2S)-2-(2-(2,3-difluoro-5-((1R,3S)-3-methylcyclobutoxy)phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)cyclopropanecarboxylicacid; 84)2-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-cyclo-propanecarboxylicacid; 85)(1R,2R)-2-{2-[5-(cyclobutyloxy)-2,3-difluorophenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}cyclopropane-carboxylicacid; 86)(1R,2R)-2-{2-[3-chloro-5-(cyclobutyloxy)-2-fluorophenyl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 87)(1R,2R)-2-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}cyclopropanecarboxylicacid; 88)(1S,2S)-2-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}cyclopropanecarboxylicacid; 89)(1R,2R)-2-(2-{3-cyano-2-fluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 90)(1S,2S)-2-{2-[2-fluoro-5-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}cyclopropanecarboxylicacid; 91)(1S,2S)-2-{2-[3-chloro-5-(cyclobutyloxy)-2-fluorophenyl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 92)2-{2-[4-fluoro-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 93)(1S,2S)-2-{2-[3-chloro-2-fluoro-5-(trifluoromethyl)benzyl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 94)2-{2-[4-fluoro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 95)2-{2-[4-fluoro-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 96)2-{2-[4-fluoro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 97)(1S,2S)-2-(2-{2-cyano-3-methoxy-5-[(trans-3-methoxycyclobutyl)oxy]-phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 98)(1S,2S)-2-(2-{2,3-difluoro-5-[(trans-3-methylcyclobutyl)oxy]phenyl}-1,2,3,4-tetra-hydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 99)(1R,2R)-2-(2-{2,3-difluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 100)(1S,2S)-2-(2-{2,3-difluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 101)(1R,2R)-2-(2-{2,3-difluoro-5-[(trans-3-methylcyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 102)2-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-cyclopropanecarboxylicacid; 103)(1R,2R)-2-(2-{2-cyano-3-fluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 104)2-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}cyclopropanecarboxylicacid; 105)2-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-6-yl}cyclopropanecarboxylicacid; 106)(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methoxycyclobutoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 107)(1S,2S)-2-(2-(3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 108)(1S,2S)-2-(2-(2,3-difluoro-5-((1r,3S)-3-methylcyclobutoxy)phenyl)-4-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 109)(1R,2R)-2-{2-[3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 110)(1R,2R)-2-(2-{2,3-difluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 111)(1R,2R)-2-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 112)(1R,2R)-2-(2-{2,3-difluoro-5-[(trans-3-methylcyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 113)(1R,2R)-2-{5-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}cyclopropanecarboxylicacid; 114)(1R,2R)-2-{2-[3-chloro-5-(cyclobutyloxy)-2-fluorophenyl]-1,2,3,4-tetra-hydroisoquinolin-6-yl})cyclopropanecarboxylicacid; 115)(1S,2S)-2-(2-{2,3-difluoro-5-[(trans-3-methoxycyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 116)(1S,2S)-2-{2-[3-cyano-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 117)(1S,2S)-2-{2-[2-cyano-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 118)(1S,2S)-2-{5-fluoro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}cyclopropanecarboxylicacid; 119)(1S,2S)-2-{2-[2-cyano-3-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 120)(1S,2S)-2-{2-[3-chloro-2-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 121)(1R,2R)-2-{2-[2-chloro-3-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 122)(1S,2S)-2-(2-{2,3-difluoro-5-[(trans-3-methylcyclobutyl)oxy]phenyl}-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclopropanecarboxylicacid; 123)(1R,2R)-2-{2-[3-chloro-5-(cyclobutyloxy)-2-fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylic acid; 124)(1S,2S)-2-{2-[2-chloro-3-fluoro-5-(trifluoromethoxy)phenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 125)(1S,2S)-2-{2-[3-chloro-5-(cyclobutyloxy)-2-fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)}cyclopropanecarboxylicacid; 126)(1S,2S)-2-{2-[2-cyano-5-(cyclobutyloxy)-3-fluorophenyl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}cyclopropanecarboxylicacid; 127)5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)pentanoicacid; 128)5-(2-(4-cyano-3-methyl-1-(p-tolyl)-1H-pyrazol-5-yl)-1,2,3,4-tetrahydroiso-quinolin-6-yl)hexanoicacid; 129)5-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile;130)5-(6-(2-hydroxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(p-tolyl)-1H-pyrazole-4-carbonitrile;131)3-(2-(5-cyclobutoxy-2,3-difluorophenyl)-7-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl)-propanoicacid; 132)6-(2-(1H-tetrazol-5-yl)ethyl)-2-(2,3-difluoro-5-((1r,3r)-3-methoxylcyclo-butoxy)-phenyl)-1,2,3,4-tetrahydroisoquinoline;133)5-{2-[4-cyano-1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}pentanoicacid; 134)5-{2-[4-cyano-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}pentanoicacid; 135)5-{2-[2-fluoro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-pentanoicacid; 136)5-[6-(2-hydroxyethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-3-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile;137)5-{2-[4-chloro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}pentanoicacid; 138)5-(6-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile;139)5-[6-(4-hydroxybutoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-3-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile;140)5-{2-[4-cyano-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}hexanoicacid; 141)5-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile;142)5-{2-[4-cyano-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-isoquinolin-6-yl}hexanoicacid; 143)3-(2-{[4-fluoro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoicacid; 144)5-[6-(3-hydroxypropoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-3-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile;145)3-{2-[5-(cyclobutyloxy)-2,3-difluorophenyl]-7-fluoro-1,2,3,4-tetrahydroiso-quinolin-6-yl}propanoicacid; 146)3-{2-[4-chloro-3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-5-fluoro-1,2,3,4-tetrahydro-isoquinolin-6-yl}propanoicacid; 147)3-{2-[3-chloro-2-cyano-5-(cyclobutyloxy)phenyl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 148)3-{2-[5-cyano-4-(cyclobutyloxy)-6-methylpyrimidin-2-yl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 149)3-{2-[5-cyano-2-(cyclobutyloxy)-6-methylpyrimidin-4-yl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 150)3-{5-chloro-2-[2-cyano-5-(cyclobutyloxy)-3-fluorophenyl]-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 151)3-[2-(6-cyclopropylpyridin-2-yl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl]-propanoicacid; 152)3-{2-[2-cyano-5-(cyclobutyloxy)-3-fluorophenyl]-5-fluoro-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 153)3-{2-[2,3-dichloro-5-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 154)3-{2-[2-cyano-5-(cyclobutyloxy)-3-fluorophenyl]-5-methyl-1,2,3,4-tetra-hydroisoquinolin-6-yl}propanoicacid; 155)3-{2-[6-(cyclobutyloxy)-3-fluoro-4-methoxypyridin-2-yl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; 156)3-{2-[3-cyano-6-(cyclobutyloxy)-2-methylpyridin-4-yl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; and 157)3-{2-[3-cyano-4-methyl-6-(1,3-thiazol-4-yl)pyridin-2-yl]-5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl}propanoicacid; or a pharmaceutically acceptable salt thereof.
 18. Apharmaceutical composition comprising a compound of claim 1 incombination with a pharmaceutically acceptable carrier.
 19. (canceled)20. (canceled)
 21. (canceled)
 22. A method for the treatment of acondition selected from the group consisting of diabetes,hyperlipidemia, obesity, and inflammation related disorders comprisingadministering to an individual a pharmaceutical composition comprisingthe compound of claim 1.